[Frontiers in Bioscience 14, 847-871, January 1, 2009]
Post-transcriptional gene regulation by MAP kinases via AU-rich elements
Andrew Clark, Jonathan Dean, Corina Tudor, Jeremy Saklatvala
Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK
TABLE OF CONTENTS
1. ABSTRACT
Eukaryotic cells must continuously sense their environments, for example their attachment to extracellular matrix and proximity to other cells, differences in temperature or redox conditions, the presence of nutrients, growth factors, hormones, cytokines or pathogens. The information must then be integrated and an appropriate response initiated by modulating the cellular programme of gene expression. The mitogen-activated protein kinase (MAPK) signaling pathways play a critical role in this process. Decades of research have illuminated the many ways in which MAPKs regulate the synthesis of mRNA (transcription) via phosphorylation of transcription factors, cofactors, and other proteins. In recent years it has become increasingly clear that the control of mRNA destruction is equally important for cellular responses to extracellular cues, and is equally subject to regulation by MAPKs. This review will summarize our current understanding of post-transcriptional regulation of gene expression by the MAPKs and the proteins that are involved in this process.
2. INTRODUCTION
The orderly and regulated flow of genetic information from DNA to protein, from genome to proteome, requires that the intermediate molecule, mRNA, is relatively short-lived. Where gene expression undergoes dynamic changes, rapid turnover of mRNA is typically observed. For example mRNAs involved in cell cycle progression, immune and inflammatory responses often have short half-lives. In contrast housekeeping genes that are expressed at a relatively constant level typically produce more stable mRNAs (1). In other words mRNA degradation is controlled in a transcript-specific manner. In most cases the rate of degradation of an mRNA is controlled by sequences within its untranslated regions (UTRs). These regions are unconstrained by the selective pressures that direct the evolution of protein coding sequences, and have acquired complex roles in the regulation of mRNA translation and localisation as well as turnover.
Post-transcriptional regulation of gene expression is comprehensively reviewed elsewhere (2, 3), and only a very brief overview will be given here (Fig 1). In general the rate limiting step in mRNA degradation is the shortening of the poly- (A) tail with which the 3' end is decorated. This can be catalysed by a number of different deadenylases or deadenylase complexes. Once the poly (A) tail has been shortened beyond a critical length, the body of the mRNA becomes susceptible to rapid destruction by one of two pathways. The first pathway involves the exosome, a large complex of exonucleases and helicases responsible for processive degradation from the 3' end. When the bulk of the mRNA has been destroyed and only a short oligoribonucleotide remains, a scavenger decapping complex removes the 7-methyl-guanosine cap from the 5' end. Alternatively, the mRNA can be degraded by the exonuclease Xrn1, which degrades in the 5' to 3' direction. This pathway requires the initial removal of the 7-methyl-guanosine cap, which is catalysed by a decapping complex distinct from the scavenger decapping complex mentioned above. Both pathways for mRNA degradation are extremely rapid, and intermediates are difficult to detect. It was initially believed that the 3' to 5' exosome-dependent pathway predominated in mammalian cells, but more recent evidence suggests that the 5' to 3' pathway may be equally important (2, 4). RNA degradation may occur at discrete cytoplasmic granules known as processing bodies or P-bodies, which are also implicated in micro-RNA mediated post-transcriptional silencing and RNA surveillance pathways (5-7).
Regulatory elements in UTRs are recognized in a sequence-specific manner by RNA-binding proteins. Whilst other classes of regulatory element and their binding proteins are increasingly recognized, the best characterized regulatory sequences at present are the adenine/uridine-rich elements (AREs), first described as mRNA destabilizing elements in 1986 (8, 9). In a commonly used classification based on the presence of pentameric AUUUA motifs, type I AREs contain dispersed pentamers, type II AREs contain overlapping pentamers, and type III AREs contain no pentamers but are generally U-rich . Other classification systems have also been proposed (10). The nonameric sequence UUAUUUAUU was identified as a minimal destabilizing sequence (11, 12), but other ARE sequences may function equally well, depending on the context in which they are found.
Many ARE binding proteins have been identified, and shown to recognize AREs with overlapping but subtly different sequence specificities (2, 3). Amongst these proteins, tristetraprolin (TTP) and two closely related proteins are well-characterized mRNA destabilizing factors, as is the KH-domain splicing regulatory protein (KSRP). Human antigen R (HuR), a widely-expressed member of the ELAV (embryonic lethal abnormal vision) family of RNA binding proteins, is a stabilizing factor. ARE/poly (U)-binding degradation factor 1 (AUF1) may either promote or inhibit mRNA degradation, depending on the cellular context and which of the four alternatively spliced isoforms are expressed. Destabilizing factors recruit components of the RNA degradation machinery to specific mRNAs, or cause those RNAs to become localized at sites of degradation, or nucleate the formation of processing bodies (13-20). In effect these may amount to the same thing.
mRNA fate is thought to be determined by the combinatorial actions of multiple proteins that recognize overlapping or discrete sequences within UTRs. In ways that are not yet fully understood, their binding is likely to be influenced by the secondary structure of the mRNA, which in turn may be influenced by ionic conditions (21) or intermolecular RNA-RNA interactions (22). The cellular machinery dedicated to the destruction of RNA is therefore highly complex, with many possible points of regulation. Indeed, the process of mRNA turnover is under tight regulation, and can be modulated in response to extracellular cues. Hence changes in mRNA abundance can be brought about by changes in rate of synthesis, destruction or both. Post-transcriptional mechanisms can function cooperatively with transcriptional mechanisms to accelerate or amplify changes in steady state mRNA levels. Alternatively, transcriptional and post-transcriptional mechanisms can oppose one another to dampen changes in steady state mRNA levels.
Researchers have recently used microarray-based approaches to assess the relative contributions of transcriptional and post-transcriptional regulatory events during a coordinated cellular response (23, 24). For example changes in steady state cytoplasmic mRNA abundance were compared to changes in newly synthesized nuclear pre-mRNA, the latter providing a crude measure of the transcriptional response (25, 26). It was concluded that approximately half of the global change in mRNA levels could be accounted for by transcriptional regulation. By inference, the remainder must be explained by changes in mRNA stability. More directly, other researchers have combined microarrays with actinomycin D chases to study mRNA stability at a transcriptome-wide level (27-30). Half-lives of many thousands of mRNAs were increased or decreased in the course of a cellular response to a simple agonist. Such studies underline the point that changes in cellular programmes of gene expression cannot be understood in terms of transcription alone. It is increasingly recognized that alterations in post-transcriptional regulatory mechanisms can have a causative role in human pathologies, for example cancers and chronic inflammatory diseases (31-35). Conversely, the post-transcriptional level of gene regulation represents a possible new target for therapeutic intervention in human disease (36, 37).
The principles of transcriptional regulation by signaling pathways are quite well understood. In contrast the study of mRNA turnover regulation is in its infancy. This review will focus on modulation of mRNA stability by MAPKs, highlighting gaps in our current understanding of this phenomenon. Table 1 lists mRNAs that have been identified as targets of post-transcriptional regulation by the three major MAPK pathways. There is more abundant evidence for post-transcriptional regulation by p38 than by ERK or JNK, therefore our review will begin with the p38 MAPK pathway.
3. POST-TRANSCRIPTIONAL REGULATION BY MAPK PATHWAYS
3.1. p38 MAPK
The four members of the p38 MAPK family, abg and d, are encoded by discrete genes and display different patterns of tissue-specific expression (38). The a isoform is very broadly expressed whereas the other isoforms are expressed in a more restricted fashion. The first member of the family, p38a, was identified at about the same time by three labs as a component of a signaling pathway activated by the pro-inflammatory cytokine interleukin 1 (IL-1) or by stresses such as heat shock or hyperosmolarity, and as the molecular target of a novel compound that post-transcriptionally inhibited the expression of IL-1 and another potent inflammatory cytokine, tumor necrosis factor (TNF). Since its discovery, the p38 MAPK pathway has therefore been intimately linked to both inflammation and post-transcriptional regulation. In the canonical pathway an upstream MAPK kinase (usually MKK3 or MKK6) activates p38 MAPK by phosphorylating both threonine and tyrosine residues within the Thr-Gly-Tyr activation motif. Alternative pathways for p38 MAPK activation exist, one involving phosphorylation of a tyrosine residue near the carboxy terminus (39). It is conceivable that this phosphorylation modulates the interaction of p38 MAPK with downstream substrates, and that therefore the outcome of p38 MAPK activation depends upon the pathway by which it becomes active. It has not yet been investigated whether non-canonical p38 MAPK activation has different consequences in terms of post-transcriptional gene regulation.
SK&F 86002, the original p38 inhibitor, has given rise to second and third generation inhibitors such as SB203580 and SB202190, with improved specificity and efficacy. These drugs, which have played an essential part in the elucidation of the post-transcriptional function of the p38 MAPK pathway, do not inhibit the g or d isoforms (40). A recently described class of MAPK inhibitors is mechanistically dinstinct from the original family of dipyridinyl imidazoles, and blocks the function of all four isoforms (41). Such compounds may be used to determine whether p38 g and d are involved in the post-transcriptional regulation of gene expression. They clearly differ in substrate specificity from the a and b isoforms (38), and there is yet little or no evidence for a post-transcriptional role. Henceforth "p38" will be assumed to refer to the a and b isoforms.
Because of the central role of the p38 MAPK pathway in the regulation of inflammatory gene expression, it is regarded as a promising target for therapeutic intervention in chronic inflammatory diseases such as rheumatoid arthritis or Crohn's disease (42, 43). Several p38 MAPK inhibitors have undergone or are undergoing clinical trials (44). It needs to be kept in mind that the function of p38 MAPK is not restricted to the control of inflammatory gene expression. For example muscle differentiation requires the p38-dependent expression of transcription factors such as MyoD and myogenin (45, 46). Other roles in cell proliferation and survival, differentiation or development have been described (38). It is not yet apparent whether these additional p38 functions will give rise to significant problems in the clinical development of p38 inhibitors as anti-inflammatory drugs (47).
Early papers concluded that the p38 MAPK pathway was required for the efficient translation of TNF mRNA, because inhibitors reduced TNF expression more strongly at the protein level than at the mRNA level (48, 49). However, recent research (Table 1) has revealed that control of mRNA stability is a more frequently encountered property of the p38 pathway. In fact, several studies describe destabilization of TNF mRNA by p38 inhibitors (50-55). As described below, mechanisms of regulation of mRNA turnover by p38 MAPK are increasingly well understood, but an account of transcript-specific translational control by this pathway is still lacking.
It is technically difficult to quantify changes in translation efficiency in isolation from mRNA degradation. In the absence of such direct assays, translational control is often inferred from inspection of polysomal profiles or from discrepancies between mRNA and protein levels. In the case of TNF the correlation between mRNA and protein expression tends to be poor (56-60). Even under strongly inducing conditions, a relatively low proportion of TNF mRNA may be actively translated and associated with polysomes (48, 60-63). Deductions from mRNA and protein abundance can be misleading if discrete subcellular pools of TNF mRNA are not identically regulated by signaling pathways. For example (Fig 2) suppose that there exists a subcellular pool of TNF mRNA (pool 1), which is unavailable for translation and not regulated by p38 MAPK at the level of mRNA stability. In contrast, p38 MAPK controls the stability of a second, discrete subcellular pool (pool 2), which is available for translation. If the majority of TNF mRNA is in pool 1, then inhibition of p38 will strongly decrease expression of TNF protein but not strongly decrease whole-cell levels of TNF mRNA. Inhibitors of p38 MAPK are reported to decrease the proportion of TNF mRNA associated with polysomes (48, 62), which has been interpreted as suggesting that p38 promotes the translation of TNF mRNA. However there is not yet direct evidence that TNF mRNA can be mobilized between untranslatable and translatable pools in a manner that is controlled by p38 MAPK. An alternative interpretation of the same data is that inhibition of p38 MAPK causes the degradation rather than the translational suppression of polysome-associated TNF mRNA.
Effects of p38 MAPK on mRNA translation certainly cannot be ruled out, although the lack of a mechanistic explanation is problematic, and the supporting evidence is not as conclusive as it may appear. The RNA binding proteins TIA-1, TIAR and FXR1P have been implicated in the sequestration and translational blockade of TNF mRNA (62, 64, 65). It is possible that one or more of these proteins acts downstream of the p38 MAPK pathway to control translation of TNF and other mRNAs, but such a role has not yet been demonstrated. Transcriptional pulsing strategies can be used to generate synchronized pools of reporter mRNAs with similar poly (A) tail lengths (66). This method was used to show that p38 activation inhibits the deadenylation of a reporter mRNA containing the TNF ARE, without influencing the rate of subsequent decay of the mRNA body (67). Poly (A) tail length influences the efficiency of mRNA translation as well as its stability. In theory, control of deadenylation by p38 MAPK could provide a mechanistic link between effects of the pathway on mRNA translation and stability. However, it is not yet well established that p38 MAPK controls stability of endogenous ARE-containing transcripts at the level of deadenylation.
The downstream kinase MAPK-activated protein kinase 2 (MAPKAP-K2 or MK2) is efficiently phosphorylated and activated by p38 a and b but not by the g and d isoforms (38, 68-71). Several lines of evidence suggest that MK2 has an important role as an effector of post-transcriptional regulation by the p38 MAPK pathway. Constitutively active mutants of MK2 were able to stabilize a variety of ARE-containing reporter transcripts (72-76). An MK2 null mouse was viable but underexpressed several inflammatory mediators that are post-transcriptionally regulated by the p38 MAPK pathway (71, 77-79), and was consequently resistant to various inflammatory challenges (80-83). Initially, steady state levels and stability of TNF mRNA were found to be unaltered in MK2-/- cells in spite of an approximately 90% decrease in expression of TNF protein, consistent with regulation of TNF translation by the p38 MAPK pathway (77). However, on further investigation, both TNF and IL-6 mRNAs were found to be less stable in cells lacking MK2 (79, 84). In embryonic fibroblasts derived from MK2-/- mice, a subset of mRNAs (including, CSF2, CXCL1, CXCL2, COX-2) were unstable in the presence of LPS but could be stabilized by reintroduction of MK2 (78), implying that LPS-induced stabilization requires the activation of MK2.
The kinase MK3 is highly related to MK2 and appears to overlap in function. The dominant role of MK2 in post-transcriptional regulation may simply reflect its higher level of expression in the cell types that have been studied. A murine knockout of MK3 alone had no obvious consequences, but in an MK2 null background caused a further decrease in the expression of TNF. Furthermore MK3 was indistinguishable from MK2 in its ability to rescue mRNA stabilization in MK2-/- MEFs (78). The functions of MK2 and MK3 have been investigated mainly in the context of inflammatory gene expression. An unanswered question is to what extent the regulation of mRNA stability is independent of MK2 or MK3, in other words directly mediated by p38 MAPK itself. It would be interesting to determine which mRNAs, if any, are destabilized by p38 inhibitors in the absence of both MK2 and MK3. Since different mechanisms of post-transcriptional regulation by the p38 pathway might predominate in different cell types, it would be instructive to carry out such an analysis in, for example, muscle cells as well as fibroblasts or macrophages.
The TNF ARE is essential for post-transcriptional control of TNF expression by p38 MAPK, since germline deletion of this element rendered TNF biosynthesis insensitive to p38 inhibitors (85). AUUUA motifs are common to p38-regulated transcripts (86), but their number and organization is extremely variable. A relatively complex arrangement of AUUUA motifs appeared to be necessary for regulation of COX-2 or IL-8 mRNA stability by the p38 pathway (87, 88). Amongst p38-stabilized mRNAs identified in a microarray study (29) common features of ARE sequence or structure could not be identified. Just as importantly, many unstable ARE-containing transcripts were not sensitive to p38 inhibition. Therefore, one of the greatest remaining puzzles in this field is how selective regulation of mRNA stability by the p38 pathway is achieved. To understand this fully it may be necessary to consider the secondary structure of RNA in which protein binding sites are embedded, or higher order features of ARE organization that have not yet been recognized.
3.2. ERK and JNK
Stability of several mRNAs has been shown to be regulated by the extracellular signal-regulated kinase (ERK) pathway (Table 1). There is considerable overlap with the set of transcripts regulated by p38 MAPK. Furthermore, CXCL2 and TNF mRNAs were cooperatively stabilized through the action of p38 MAPK and ERK (52, 89-91). The possible significance of convergence of the two signaling pathways is discussed below.
In macrophages the activation of ERK is required for the efficient export of TNF mRNA from the nucleus to the cytoplasm (92). The TNF ARE is necessary but not sufficient for this regulation, and ARE-binding proteins involved have so far not been identified (92, 93). The regulation of TNF mRNA export is dependent on nuclear splicing of pre-mRNA and assembly of a complex of proteins at the splice site (93). Few other examples of ERK-regulated nuclear-cytoplasmic mRNA transport are known (94), and details of the mechanism await clarification.
The c-Jun N-terminal kinase (JNK) pathway was implicated in post-transcriptional regulation of IL-2 and -3, TNF, inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) (references in Table 1). The synthetic glucocorticoid dexamethasone (dex) was reported to block TNF translation by inhibiting JNK activity in a mouse macrophage cell line (95). Dex also inhibits p38 MAPK in murine macrophages by inducing the expression of MAPK phosphatase 1 (57, 96, 97), therefore the inference that JNK controls translation may be mistaken. JNK-mediated stabilization of IL-2 mRNA was dependent on both an ARE in the 3' UTR and an element in the 5' UTR, designated the JNK response element (JRE) (98, 99). The JRE was recognized by nucleolin, an abundant nucleolar protein (100), and Y-box factor 1 (YB-1), a promiscuous nucleic acid binding protein (101). Depletion of these factors impaired JNK-mediated mRNA stabilization in vitro. However, neither protein appears to be a genuine substrate of JNK or a direct regulator of mRNA degradation. Their roles in mRNA turnover downstream of JNK may be rather indirect (99). Direct mechanistic links between JNK and mRNA stability or translation remain elusive.
3.3. MAPK signal integrating kinases
MAPK signal-integrating kinases (Mnks) can be activated by either p38 MAPK or ERK, and are therefore potential mediators of cooperative effects of the two MAPK pathways on gene expression (102, 103). Mnks are thought to influence higher order structure of mRNAs and control translation by phosphorylating the eukaryotic translation initiation factor eIF4E, which binds to the 5' cap structure (references in 104). It is unclear how this mechanism could result in selective post-transcriptional regulation of particular transcripts, since the 5' cap is a universal feature of eukaryotic mRNAs. Therefore it is of interest that Mnks are also able to phosphorylate hnRNPA0, hnRNPA1 and polypyrimidine tract binding protein-associated splicing factor (PSF) (104, 105). All of these proteins have been shown to interact with AREs, although precise specificities are not known. A Mnk inhibitor, CGP57380, decreased the expression of TNF in Jurkat T cells (104), murine macrophages (106) human keratinocytes (107) and the murine macrophage cell line RAW264.7 (108). The same inhibitor increased the association of TNF mRNA with hnRNPA1 but decreased its association with PSF in Jurkat cells (104, 105). Mnks are proposed to regulate the translation (104, 106) and/or stability (108) of TNF mRNA through the phosphorylation of one or more associated RNA binding proteins. The specificity of CGP57380 is imperfect (40), therefore it would be extremely valuable to confirm these findings in the Mnk1/Mnk2 knockout mouse (109).
4. MEDIATORS OF POST-TRANSCRIPTIONAL REGULATION BY MAPKS
4.1. Tristetraprolin
Tristetraprolin (TTP) is a member of a small family of RNA-binding proteins that recognize AREs via a conserved, central tandem zinc finger domain (110) (Fig 3). Amongst several alternative names, TTP is also known as ZFP36 (zinc finger protein of 36 kD). In general, TTP protein is weakly expressed under basal conditions but upregulated in response to a variety of agonists. At least in murine macrophages, the expression of TTP is dependent on p38 MAPK (74, 111, 112). TTP may bind to AREs within its own 3' UTR and autoregulate its expression (74, 113), although this idea remains controversial (114). The function of endogenous TTP protein has been investigated in cells of the myeloid lineage, and more recently in T cells (115, 116), B cells (117) and fibroblasts (114). In transient transfection experiments we observed destabilization of reporter mRNAs by quantities of exogenous TTP that were below the limit of detection. IL-1 or PMA induced the expression of TTP in HeLa cells, although the abundance of the protein remained so low that it could be detected only with some difficulty (our unpublished observations). Great care needs to be taken before describing a given cell line as "TTP null" (88, 118).
The TTP relatives BRF (butyrate response factor) 1 and 2 are also known as ZFP36-like proteins 1 and 2 (ZFP36L1 and ZFP36L2). At the mRNA level, ZFP36, ZFP36L1 and ZFP36L2 are expressed widely but at different levels in normal human tissues (119). The three proteins appear to bind RNA with similar specificity, and function identically as effectors of ARE-dependent mRNA decay, suggesting that redundancy may exist between the members of the family (15, 17, 120, 121). Yet murine knockouts of TTP and ZFP36L1 differ strikingly. The ZFP36L1 knockout is embryonic lethal, at least partly due to dysregulation of VEGF expression in the developing embryo (122, 123). As discussed below, the TTP knockout is not embryonic lethal but has an inflammatory phenotype. An authentic ZFP36L2-null mouse has not yet been generated (124). The ZFP36 proteins may serve different functions by virtue of different patterns of expression, subtle differences in RNA binding specificity that have so far escaped detection, or different mechanisms of regulation.
A number of studies have independently concluded that TTP specifically recognizes the sequence UUAUUUAUU (125-127). This sequence was highly enriched amongst transcripts that associated with TTP protein in vivo (128). Wright and colleagues (129) have solved the structure of a nonameric UUAUUUAUU oligoribonucleotide in complex with the RNA-binding domain of the ZFP36L2. A conformational change is thought to take place on binding of ZFP36L2 to its RNA substrate. The zinc finger domain of TTP is very closely related to that of ZFP36L2 and is thought to interact with substrate in a similar fashion, with a structural change induced by nucleic acid binding (126, 130). Like several other RNA-binding proteins, TTP can shuttle between the nucleus and the cytoplasm, but is almost exclusively cytoplasmic under most conditions. Several protein motifs have been implicated in the nuclear export and import of TTP (131-135). Of most direct relevance, the binding of 14-3-3 proteins to serine 178 was implicated in the cytoplasmic accumulation of murine TTP (135). 14-3-3 proteins are multifunctional adaptor proteins that specifically recognize serine- or threonine-phosphorylated partner proteins and control phosphorylation-dependent phenomena such as subcellular localization and protein stability (136-138). The implication is that cytoplasmic localization of TTP is partly dependent on phosphorylation of serine 178, as we will discuss below.
In vitro and in transfected cells TTP promotes the deadenylation of ARE-containing reporter transcripts (20, 139-141). Furthermore TTP and ZFP36L1 interact with several components of the cellular mRNA degradation machinery, including deadenylases, decapping complexes and exonucleases (14, 15, 17, 18, 20). Tethering of TTP protein to reporter mRNAs resulted in localization of those transcripts to processing bodies and rapid degradation (14, 15, 17). Depletion of TTP and ZFP36L1 impaired, whereas overexpression of TTP or ZFP36L1 enhanced, the localization of ARE-containing reporter transcripts to processing bodies (17). In these studies exogenous TTP and TTP fusion proteins were expressed without deliberate activation or inhibition of the signaling pathways that are thought to control expression and function of endogenous TTP. It would be interesting to determine whether activation of MAPK signaling pathways and phosphorylation of specific residues influenced the localization or turnover of a reporter transcript to which TTP was tethered.
The murine TTP knockout results in a complex inflammatory syndrome characterized by myeloid hyperplasia, cachexia, erosive arthritis, dermatitis and conjunctivitis (110, 142). Much of this pathology is due to enhanced stability of TNF mRNA and increased expression of TNF protein by cells of the myeloid lineage (142-144). The phenotype is likely to be influenced by dysregulation of other transcripts in both myeloid and other cell types. TTP-/- animals or cells show abnormal expression of CSF2 (colony stimulating factor 2, also known as granulocyte/macrophage colony stimulating factor), COX-2, IL-2, CXCL1 and a number of other immune/inflammatory mediators (116, 140, 145, 146) (our unpublished observations). Of particular interest, TTP directly controls expression of the potent anti-inflammatory cytokine IL-10 via its interaction with the IL-10 3' UTR (128) (our unpublished observations). Hence the TTP null phenotype may be a complex outcome of changes in expression of both pro- and anti-inflammatory mediators. In summary, TTP is well characterized as an important effector of ARE-dependent mRNA degradation. Several targets of TTP-mediated post-transcriptional regulation have been identified, and other putative targets are coming to light, for example through the systematic analysis of mRNA stabilities in TTP null fibroblasts (114) or by analysis of transcripts associated with TTP in vivo (128).
TTP is very extensively phosphorylated in vivo (112, 147-149). Mass spectrometric analysis identified ten major sites of phosphorylation of exogenously expressed TTP in HEK293 cells, as well as several minor sites (149). It should be noted that signaling pathways involved in the phosphorylation of TTP may not have been fully active in these cells, since no stimulus was applied. In vitro TTP could be phosphorylated by all three major MAPKs (147, 150-154), although sites of phosphorylation and functional consequences are not yet known. Since p38 MAPK regulates mRNA stability via MK2, it is significant that TTP is efficiently phosphorylated by MK2 in vitro (112). Two major sites of phosphorylation by MK2 were identified as serines 52 and 178 (of murine TTP) (155). There is evidence that both sites are phosphorylated in vivo, and that MK2 is at least partly responsible (149, 155, 156). Note that the sequence surrounding the distal phosphorylation site is quite well conserved in ZFP36L1 and ZFP36L2 (Fig 3). The corresponding site in ZFP36L1 has been implicated in the regulation of ZFP36L1 function by PKB (157).
TTP-/- macrophages were relatively insensitive to the inhibitory effect of p38 inhibitors on TNF gene expression, suggesting that post-transcriptional gene regulation by the p38 MAPK pathway may be mediated by TTP (150). Whereas MK2-/- mice underexpressed and TTP-/- mice overexpressed TNF, double knockout mice expressed roughly the same quantity of TNF as the TTP knockouts. Therefore MK2 regulates TNF biosynthesis chiefly by inactivating TTP (84). CXCL-1 mRNA was destabilized by a p38 inhibitor in wild type macrophages but not in TTP-/- macrophages (146). The same is broadly true of TNF, IL-10 and a number of other mRNAs (our unpublished observations). One exception is that TNF mRNA was very weakly (but statistically significantly) destabilized by p38 inhibition in TTP-/- macrophages. These observations demonstrate that the p38-MK2 pathway regulates the stability of certain inflammatory mediator mRNAs exclusively (or almost exclusively) via TTP (at least in murine macrophages).
It is clearly crucial to understand what MK2-mediated phosphorylation does to TTP. The phosphorylation of serines 52 and 178 increases the interaction of TTP with 14-3-3 proteins (155, 156, 158, 159), with a highly complex set of consequences (Fig 4). 1) Prevention of dephosphorylation. The phosphorylation status of TTP is dynamically regulated by a balance of kinase and phosphatase activities (111, 156). The binding of 14-3-3 proteins protects TTP from PP2a-mediated dephosphorylation (156). The cellular equilibrium between phosphorylated and unphosphorylated TTP may therefore be set by 14-3-3 protein availability, although this remains to be tested. 2) Prevention of proteasome-mediated degradation. In transfected cells, coexpression of 14-3-3 proteins increased the levels of TTP protein (135). MK2-dependent phosphorylation of serines 52 and 178 prevented the proteasome-mediated degradation of TTP protein, presumably because the recruitment of 14-3-3 proteins blocks targeting of TTP to the proteasome (84, 111). 3) Regulation of subcellular localization. TTP can be detected in both stress granules (distinct cytoplasmic foci at which translationally silenced mRNAs are stored under conditions of cellular stress) and processing bodies (4, 6, 160, 161). Phosphorylation at serines 52 and 178 resulted in exclusion of TTP from stress granules (158). The significance of this is uncertain, because stress granules are not thought to be sites of mRNA degradation, and it is not known whether they are formed during a normal physiological response to a pro-inflammatory stimulus. In HeLa cells IL-1 caused transient relocalization of a GFP-TTP fusion protein from the nucleus to the cytoplasm in a manner dependent on p38 MAPK activation and intact serines 52 and 178 (our unpublished observations). The stabilization of TTP mRNA and protein by p38 MAPK (74, 84, 111) makes it difficult to observe endogenous TTP protein under conditions of chronic p38 inhibition. However, addition of a p38 inhibitor to macrophages that had previously been stimulated with LPS resulted in relocalization of pre-existing endogenous TTP to the nucleus (111). This is consistent with the previous observation that 14-3-3 proteins enhanced the cytoplasmic accumulation of TTP in a manner dependent on serine 178 (135), but its physiological significance is so far unknown. 4) Regulation of RNA binding activity. MK2-mediated phosphorylation of serines 52 and 178 was suggested to decrease the affinity of TTP for cognate RNA (84), although other studies disagreed with this conclusion (155, 156, 158). 5) Regulation of mRNA-destabilizing activity. Phosphorylation of serines 52 and 178 impaired the RNA destabilizing function of TTP. Wild type TTP destabilized an ARE-containing reporter but was inactivated by MK2, whereas a serine 52/178 mutant destabilized the reporter and was unresponsive to MK2 (158).
The p38 MAPK-MK2 pathway thus appears to have extremely complex effects on TTP. Via the regulation of mRNA stability, protein stability and localization it promotes the accumulation of cytoplasmic TTP. However this form of TTP is phosphorylated, inactive, possibly sequestered. The cell is therefore poised to rapidly degrade target mRNAs when the activity of MK2 declines and the kinase-phosphatase equilibrium shifts towards TTP dephosphorylation and activation. At the same time TTP protein becomes susceptible to proteasome-mediated destruction. An intriguing finding that merits further investigation is that the degradation of TTP target mRNAs appears to be somehow coupled to the degradation of TTP protein itself (91).
There are many other interesting questions. For example, does regulation of an mRNA by TTP imply regulation by the p38 MAPK pathway? The majority of known targets of TTP are also post-transcriptionally regulated by the p38 pathway. Novel TTP targets were recently identified by investigation of TTP-/- fibroblasts (114). The most completely characterized of these novel targets was Ier3 (immediate early response 3), which was elsewhere shown to be stabilized in a p38-dependent manner in response to Herpes simplex virus infection (162). It is not yet known whether other recently-identified targets of TTP are post-transcriptionally regulated by p38 MAPK. The question can be put another way: are all genes that are post-transcriptionally regulated by p38 MAPK targets of TTP? This is an important issue, in view of alternative mechanisms of mRNA stabilization by the p38 pathway discussed below. An informative approach might be to ask whether post-transcriptional regulation by p38 MAPK is impaired in non-myeloid cells (for example muscle cells) derived from TTP-/- mice.
A very important question is what the MK2-mediated TTP phosphorylation does if it does not impair RNA binding. An obvious hypothesis is that it blocks the interaction of TTP with one or more of the components of the mRNA decay machinery, but this has not been demonstrated. The many sites of phosphorylation of TTP suggest that it may serve as a target of post-transcriptional regulation by other kinases. Regulation of TTP function through direct phosphorylation by p38 MAPK itself cannot yet be ruled out. According to recent reports the mRNA destabilizing function of TTP could be impaired through activation of the ERK pathway (91, 163). In one case inhibition of both ERK and p38 MAPK was required for prevention of TTP-mediated mRNA decay (91). Intriguingly, ERK and p38 MAPK pathways also cooperated to regulate the stability of TTP protein (111). Although ERK is known to phosphorylate TTP (147, 152, 153), sites of phosphorylation remain to be identified. Until this is done the nature of the convergence of ERK and p38 MAPK pathways on TTP cannot be elucidated.
4.2. HuR
HuR is the only widely-expressed member of the mammalian ELAV family of RNA binding proteins, the others being restricted to neuronal cells (164). HuR is chiefly localized in the nucleus but, like TTP and many other RNA binding proteins, has the capacity to shuttle between nucleus and cytoplasm. It is clearly an mRNA stabilizing factor that binds to AREs, but it also recognizes other U-rich sequences (165). Consistent with its rather relaxed binding specificity, HuR has been implicated in the post-transcriptional control of many genes (164, 166-168). Amongst these are several genes involved in the regulation of apoptosis, therefore HuR appears to be a key coordinator of a pro-survival program (168). Like the Drosophila melanogaster orthologue ELAV, HuR is probably essential for cell survival and proliferation, and no mammalian knockout has yet been described. It is thought to be involved in the assembly of ribonucleoprotein complexes in the nucleus and their export to the cytoplasm as well as subsequent cytoplasmic events. Manipulation of cellular HuR levels may perturb early post-transcriptional events, therefore experiments involving overexpression or knockdown by RNA interference need to be interpreted with caution.
In many cancers, increased cytoplasmic expression of HuR has been linked to poor prognosis and elevated expression of pro-survival genes, in particular COX-2 (33, 167, 169, 170). Cytoplasmic accumulation of HuR is induced by several stimuli, including pro-inflammatory cytokines, ultraviolet light, T cell activation and heat shock. In many cases mRNA stabilization and cytoplasmic accumulation were both prevented by p38 MAPK inhibitors (171-176). It has therefore been suggested that p38 stabilizes target mRNAs by promoting relocalization of the stabilizing factor HuR to the cytoplasm.
We raise a number of concerns about this hypothesis. Whilst p38 MAPK is thought to regulate mRNA deadenylation (67), HuR exerts its stabilizing effect by blocking the degradation of the mRNA body, not deadenylation (176-178). Detailed analysis of COX-2 and IL-8 AREs showed that HuR binding and p38-regulated mRNA stability did not have the same sequence requirements (87, 88). Stimulation of T cells through CD3 induced relocalization of HuR from the nucleus to the cytoplasm but did not stabilize IL-2 mRNA. Costimulation through CD3 and CD28 stabilized IL-2 mRNA but did not further increase cytoplasmic levels of HuR, therefore changes in mRNA stability can be uncoupled from changes in HuR localization (179). Stabilization of mRNA by the p38 MAPK pathway can occur within less than an hour. In many of the cases that have been described, it is not clear that relocalization of HuR to the cytoplasm occurs with similar rapidity. HuR activity and/or localization are regulated directly or indirectly by the checkpoint kinase Chk2, the AMP-regulated kinase and protein kinase C (180-183). However, there is so far no mechanistic explanation for effects of the p38 MAPK pathway on HuR, through phosphorylation of HuR itself or the proteins that control its localization. Until such a link is found it remains possible that relocalization of a small fraction of cellular HuR from the nucleus to the cytoplasm does not have a direct causal role in p38-mediated mRNA stabilization. For example, assume that HuR is required for the export of several mRNAs from the nucleus, and remains associated with those mRNAs throughout their cytoplasmic life-span. The p38-mediated stabilization of a subset of those mRNAs might then lead to, rather than be caused by, an increase in cytoplasmic levels of HuR. Pending the description of a more direct link between HuR and p38 MAPK, this is offered as an alternative hypothesis.
4.3. KSRP
KH-domain splicing regulatory protein (KSRP) belongs to a small family of proteins, members of which have been implicated in the regulation of transcription, mRNA splicing, editing and localization. A recent addition to this list is the regulation of mRNA turnover. KSRP interacts with the exosome and other decay components in vivo (13, 16, 18). Depletion of KSRP inhibited the decay of ARE-containing reporter mRNAs in vitro and in vivo (13), and tethering of KSRP to reporter transcripts promoted their decay (16). KSRP is involved in post-transcriptional regulation by two distinct signaling pathways, the PI3K and p38 MAPK pathways (184-187).
The p38 MAPK pathway controls terminal differentiation of muscle cells by regulating expression of the transcription factor myogenin and the cyclin-dependent kinase inhibitor p21waf/cip, amongst several other genes (46). Myogenin and p21 mRNAs are destabilized by KSRP. Under differentiating conditions p38 MAPK is activated, phosphorylates KSRP at threonine 692, inhibits its interaction with RNA and consequently stabilizes myogenin and p21 mRNAs (186). Ten transcripts were found to bind to KSRP in HeLa cells, and to be upregulated and stabilized when KSRP was depleted by RNA interference (187). Amongst these targets, COX-2, CSF2, CXCL2, CXCL3, IL-6 and IL-8 are already known to be post-transcriptionally regulated by the p38 MAPK pathway (Table 1). KSRP is not phosphorylated by MK2 and does not mediate regulation of mRNA stability by MK2 (186, 187). Therefore, two pathways are suggested to exist for the stabilization of target transcripts by the p38 MAPK pathway, one involving the phosphorylation and inactivation of KSRP by p38 itself, the other involving phosphorylation and inactivation of TTP by MK2 (187). It remains to be resolved whether KSRP and TTP function separately or cooperate to modulate mRNA stability in response to p38 MAPK.
The RNA binding specificity of KSRP has not been characterized in detail. Considerable structural flexibility of KSRP protein is thought to underlie its capacity to recognize many different sequence elements and participate in distinct post-transcriptional processes (188). The two related proteins FBP1 (Far upstream sequence element Binding Protein 1) and FBP3 are 58% and 40% identical to KSRP, but share strongest homology within the KH domains that mediate RNA binding (Fig 3). FBP1 was identified as a HeLa cell protein interacting with the COX-2 ARE (88), and all three family members were identified by affinity purification of proteins recognizing the TNF ARE (89). The site of phosphorylation of KSRP by p38 MAPK is moderately well conserved in FBP1 but not FBP3 (Fig 3). However, it is not known whether FBP1 or FBP3 contributes to ARE-dependent and/or p38-regulated mRNA degradation. KSRP, at least, appears to be a p38-sensitive effector of mRNA decay, but it is unclear whether the specificity of gene regulation by the p38 MAPK pathway can be accounted for by KSRP alone. Possibly the recruitment of KSRP to target transcripts is influenced by other RNA binding proteins that have greater sequence specificity.
4.4. The AUF family
AUF1 was amongst the first ARE-binding proteins to be recognized (2, 3, 189). TNF and IL-1b mRNAs were unusually stable in macrophages derived from an AUF1-/- mouse, the corresponding proteins were overexpressed in response to LPS, and AUF1-/- mice were highly susceptible to lethal endotoxic shock (190). AUF1 is therefore a critical negative regulator of innate immune responses. Four isoforms of AUF1, ranging from 37 kD to 45 kD in molecular mass, are generated by alternative splicing of the primary transcript (Fig 3). Although AUF1 is generally thought of as an mRNA destabilizing factor, it may under some circumstances exert the opposite effect. The AUF1 p37 isoform interacts with the exosome and is the principal destabilizing isoform (18, 191, 192). Post-transcriptional outcomes may depend on the relative levels of expression and subcellular localizations of the four isoforms (193-195). Databases contain a number of proteins closely related to AUF1. One of these, AUF2 (Fig 3), shows strong similarity with AUF1 in terms of its genomic organization, alternative splicing, RNA binding specificity and function (196). AUF2 and other related proteins have been little studied in the context of mRNA stability. It is not clear whether the members of this family have distinct functions or patterns of expression.
MAPKs phosphorylate serine and threonine residues followed by proline residues. Certain phosphorylated Ser-Pro and Thr-Pro sites are recognized by the peptidyl isomerase Pin1, which catalyzes cis-trans isomerization about the proline peptide bond, and thus brings about signaling-dependent changes in protein structure and function (197, 198). Pin1 was associated with AUF1 in vivo. Inhibition of Pin1 activity decreased the stability of CSF2 mRNA and increased its association with AUF1 (192, 199). These observations are consistent with a model in which phosphorylation of AUF1 converts it into a substrate for Pin1, isomerization of AUF1 inhibits its interaction with CSF2 mRNA and results in stabilization of that transcript.
The ERK pathway controls CSF2 mRNA stability (200) and has been tentatively linked to the Pin1-mediated modulation of mRNA stability (192, 199). However, the p45 isoform of AUF1 contains only three potential sites of phosphorylation by proline-directed kinases, only one of which (S83) has been shown to be phosphorylated in vivo. Glycogen synthase kinase 3b rather than ERK was implicated in the phosphorylation of S83; stimulation of the myeloid cell line THP-1 with PMA (a classical activator of the ERK pathway) resulted in loss rather than gain of phosphorylation of S83; and the phosphorylation of this site did not appear to influence affinity for an ARE substrate (201, 202). Furthermore S83 is encoded by exon 2 and is therefore not present in the p37 isoform of AUF1 that is considered the main effector of mRNA degradation. Although Pin1 appears to play a role in the regulation of mRNA stability, it remains to be demonstrated conclusively that AUF1 is the principal target, and the connection with ERK or other MAPK pathways remains to be established.
4.5. Other mediators of post-transcriptional regulation by MAPKs
Heterogeneous nuclear ribonucleoprotein (hnRNP) A0 (89) and poly (A) binding protein (203) were independently identified as ARE-binding proteins that could be phosphorylated by MK2. In both cases the relevance of such phosphorylation to p38-mediated post-transcriptional regulation remains to be demonstrated.
Translation and turnover of mRNAs are regulated not only by sequence-specific RNA binding proteins but also by short non-coding RNAs known as micro RNAs or miRNAs. Interactions between miRNAs and mRNAs are nucleated by base-pairing between the seven nucleotide "seed region" of the miRNA and a complementary sequence of the target mRNA, most often within the 3' UTR. As described in recent reviews (204-207), miRNAs are now believed to target approximately 30% of eukaryotic protein-coding mRNAs, and to contribute to the regulation of many biological phenomena. At least in part, ARE-dependent and miRNA-mediated post-transcriptional regulation share a subcellular location, the processing body (5-7). There are several possible mechanisms of crosstalk between the two post-transcriptional mechanisms, a few of which have been described in recent publications. 1) Biogenesis of miRNAs may be regulated by MAPKs at the level of transcription or processing of the precursor RNA. For example expression of miR-155 in response to immune or inflammatory activation is dependent on JNK and/or ERK pathways (208, 209). 2) Protein components of the miRNA-mediated silencing machinery could be phosphorylated and regulated by MAPK pathways. To our knowledge this has not yet been reported. 3) miRNAs could participate in the regulation of mRNA stability or translation by sequence-specific RNA binding proteins. The miRNA miR-16 and RNA-induced silencing complex (RISC) were implicated in the regulation of mRNA stability by TTP (210). Curiously, it is not the seed region of miR-16 that is complementary to the ARE core sequence AUUUA, as might be expected for a conserved mechanism of ARE-dependent control. It is also unclear whether the simultaneous binding of a complementary miRNA and RISC proteins could be consistent with the direct, high affinity interaction of TTP with an RNA substrate. 4) If miRNAs and RNA-binding proteins recognize identical or overlapping sequences, then MAPK-mediated regulation of protein binding could indirectly influence the miRNA pathway. Conversely, changes in expression of miRNAs could antagonize or augment post-transcriptional regulation by RNA-binding proteins (207). These possibilities have not yet been explored in detail.
5. SUMMARY AND PERSPECTIVE
The study of stimulus-dependent modulation of mRNA stability is relatively new. Although significant advances have been made during the last few years, several major challenges remain. This review has focussed on ARE-binding proteins, but proteins with quite different RNA-binding specificities are becoming recognized as mediators of signal-dependent changes in the translation or degradation of mRNA. It is still not well understood how the primary sequence and secondary structure of an endogenous mRNA determines its interactions with all of these proteins in vivo, and how such interactions permit signaling pathways to exert tight control over specific subsets of transcripts. Even amongst well-known and much-studied regulators of mRNA stability, it is unclear how much functional redundancy exists between closely related family members. Although certain important phosphorylation events have been identified, we do not yet know what these phosphorylations mean in terms of the localization of target mRNAs and their interactions with the cellular mRNA degradation machinery. We have described some processes involved in the signal-dependent stabilization of mRNAs. The reverse phenomenon, signal-dependent mRNA destabilization, may be equally important but has not yet been studied in detail. Finally, an area of interest for future research will be the convergence of post-transcriptional mechanisms that depend on sequence-specific protein-RNA or RNA-RNA interactions, and the impact of MAPK signalling on the interactions of the two distinct machineries.
6. ACKNOWLEDGEMENTS
The authors acknowledge support of the Arthritis Research Campaign and the Medical Research Council, UK.
7. REFERENCES
1. Yang, E., E. van Nimwegen, M. Zavolan, N. Rajewsky, M. Schroeder, M. Magnasco & J. E. Darnell, Jr.: Decay rates of human mRNAs: correlation with functional characteristics and sequence attributes. Genome Res, 13, 1863-72 (2003)
2. Garneau, N. L., J. Wilusz & C. J. Wilusz: The highways and byways of mRNA decay. Nat Rev Mol Cell Biol, 8, 113-26 (2007)
doi:10.1038/nrm2104
3. Bevilacqua, A., M. C. Ceriani, S. Capaccioli & A. Nicolin: Post-transcriptional regulation of gene expression by degradation of messenger RNAs. Journal of Cellular Physiology, 195, 356-72 (2003)
doi:10.1002/jcp.10272
4. Stoecklin, G., T. Mayo & P. Anderson: ARE-mRNA degradation requires the 5'-3' decay pathway. EMBO Rep, 7, 72-7 (2006)
doi:10.1038/sj.embor.7400572
5. Kedersha, N. & P. Anderson: Mammalian stress granules and processing bodies. Methods in Enzymology, 431, 61-81 (2007)
doi:10.1016/S0076-6879(07)31005-7
6. Eulalio, A., I. Behm-Ansmant & E. Izaurralde: P bodies: at the crossroads of post-transcriptional pathways. Nat Rev Mol Cell Biol, 8, 9-22 (2007)
doi:10.1038/nrm2080
7. Parker, R. & U. Sheth: P bodies and the control of mRNA translation and degradation. Molecular Cell, 25, 635-46 (2007)
doi:10.1016/j.molcel.2007.02.011
8. Shaw, G. & R. Kamen: A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell, 46, 659-67 (1986)
doi:10.1016/0092-8674(86)90341-7
9. Caput, D., B. Beutler, K. Hartog, R. Thayer, S. Brown-Shimer & A. Cerami: Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators. Proceedings of the National Academy of Sciences of the United States of America, 83, 1670-4 (1986)
doi:10.1073/pnas.83.6.1670
10. Halees, A. S., R. El-Badrawi & K. S. Khabar: ARED Organism: expansion of ARED reveals AU-rich element cluster variations between human and mouse. Nucleic Acids Research, 36, D137-40 (2008)
doi:10.1093/nar/gkm959
11. Lagnado, C. A., C. Y. Brown & G. J. Goodall: AUUUA is not sufficient to promote poly (A) shortening and degradation of an mRNA: the functional sequence within AU-rich elements may be UUAUUUA (U/A) (U/A). Molecular & Cellular Biology, 14, 7984-95 (1994)
12. Zubiaga, A. M., J. G. Belasco & M. E. Greenberg: The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation. Molecular & Cellular Biology, 15, 2219-30 (1995)
13. Gherzi, R., K. Y. Lee, P. Briata, D. Wegmuller, C. Moroni, M. Karin & C. Y. Chen: A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery. Molecular Cell, 14, 571-83 (2004)
doi:10.1016/j.molcel.2004.05.002
14. Fenger-Gron, M., C. Fillman, B. Norrild & J. Lykke-Andersen: Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping. Molecular Cell, 20, 905-15 (2005)
doi:10.1016/j.molcel.2005.10.031
15. Lykke-Andersen, J. & E. Wagner: Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes & Development, 19, 351-61 (2005)
doi:10.1101/gad.1282305
16. Chou, C. F., A. Mulky, S. Maitra, W. J. Lin, R. Gherzi, J. Kappes & C. Y. Chen: Tethering KSRP, a decay-promoting AU-rich element-binding protein, to mRNAs elicits mRNA decay. Molecular & Cellular Biology, 26, 3695-706 (2006)
doi:10.1128/MCB.26.10.3695-3706.2006
17. Franks, T. M. & J. Lykke-Andersen: TTP and BRF proteins nucleate processing body formation to silence mRNAs with AU-rich elements. Genes & Development, 21, 719-35 (2007)
doi:10.1101/gad.1494707
18. Chen, C. Y., R. Gherzi, S. E. Ong, E. L. Chan, R. Raijmakers, G. J. Pruijn, G. Stoecklin, C. Moroni, M. Mann & M. Karin: AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell, 107, 451-64. (2001)
doi:10.1016/S0092-8674(01)00578-5
19. Mukherjee, D., M. Gao, J. P. O'Connor, R. Raijmakers, G. Pruijn, C. S. Lutz & J. Wilusz: The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements. EMBO Journal, 21, 165-74. (2002)
doi:10.1093/emboj/21.1.165
20. Hau, H. H., R. J. Walsh, R. L. Ogilvie, D. A. Williams, C. S. Reilly & P. R. Bohjanen: Tristetraprolin recruits functional mRNA decay complexes to ARE sequences. J Cell Biochem (2006)
21. Wilson, G. M., K. Sutphen, K. Chuang & G. Brewer: Folding of A+U-rich RNA Elements Modulates AUF1 Binding. POTENTIAL ROLES IN REGULATION OF mRNA TURNOVER. Journal of Biological Chemistry, 276, 8695-704. (2001)
doi:10.1074/jbc.M009848200
22. Meisner, N. C., J. Hackermuller, V. Uhl, A. Aszodi, M. Jaritz & M. Auer: mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure. Chembiochem, 5, 1432-47 (2004)
doi:10.1002/cbic.200400219
23. Raghavan, A. & P. R. Bohjanen: Microarray-based analyses of mRNA decay in the regulation of mammalian gene expression. Brief Funct Genomic Proteomic, 3, 112-24 (2004)
doi:10.1093/bfgp/3.2.112
24. Cheadle, C., J. Fan, Y. S. Cho-Chung, T. Werner, J. Ray, L. Do, M. Gorospe & K. G. Becker: Stability regulation of mRNA and the control of gene expression. Annals of the New York Academy of Science, 1058, 196-204 (2005)
doi:10.1196/annals.1359.026
25. Cheadle, C., J. Fan, Y. S. Cho-Chung, T. Werner, J. Ray, L. Do, M. Gorospe & K. G. Becker: Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability. BMC Genomics, 6, 75 (2005)
doi:10.1186/1471-2164-6-75
26. Fan, J., X. Yang, W. Wang, W. H. Wood, 3rd, K. G. Becker & M. Gorospe: Global analysis of stress-regulated mRNA turnover by using cDNA arrays. Proceedings of the National Academy of Sciences of the United States of America, 99, 10611-6 (2002)
doi:10.1073/pnas.162212399
27. Vlasova, I. A., J. McNabb, A. Raghavan, C. Reilly, D. A. Williams, K. A. Bohjanen & P. R. Bohjanen: Coordinate stabilization of growth-regulatory transcripts in T cell malignancies. Genomics, 86, 159-71 (2005)
doi:10.1016/j.ygeno.2005.04.013
28. Raghavan, A., R. L. Ogilvie, C. Reilly, M. L. Abelson, S. Raghavan, J. Vasdewani, M. Krathwohl & P. R. Bohjanen: Genome-wide analysis of mRNA decay in resting and activated primary human T lymphocytes. Nucleic Acids Research, 30, 5529-38 (2002)
doi:10.1093/nar/gkf682
29. Frevel, M. A., T. Bakheet, A. M. Silva, J. G. Hissong, K. S. Khabar & B. R. Williams: p38 Mitogen-activated protein kinase-dependent and -independent signaling of mRNA stability of AU-rich element-containing transcripts. Molecular & Cellular Biology, 23, 425-36. (2003)
doi:10.1128/MCB.23.2.425-436.2003
30. Raghavan, A., M. Dhalla, T. Bakheet, R. L. Ogilvie, I. A. Vlasova, K. S. Khabar, B. R. Williams & P. R. Bohjanen: Patterns of coordinate down-regulation of ARE-containing transcripts following immune cell activation. Genomics, 84, 1002-13 (2004)
doi:10.1016/j.ygeno.2004.08.007
31. Conne, B., A. Stutz & J. D. Vassalli: The 3' untranslated region of messenger RNA: A molecular 'hotspot' for pathology? Nature Medicine, 6, 637-41. (2000)
doi:10.1038/76211
32. Steinman, R. A.: mRNA stability control: a clandestine force in normal and malignant hematopoiesis. Leukemia, 21, 1158-71 (2007)
doi:10.1038/sj.leu.2404656
33. Dixon, D. A.: Dysregulated post-transcriptional control of COX-2 gene expression in cancer. Curr Pharm Des, 10, 635-46 (2004)
doi:10.2174/1381612043453171
34. Lopez de Silanes, I., M. P. Quesada & M. Esteller: Aberrant regulation of messenger RNA 3'-untranslated region in human cancer. Cell Oncol, 29, 1-17 (2007)
35. Seko, Y., S. Cole, W. Kasprzak, B. A. Shapiro & J. A. Ragheb: The role of cytokine mRNA stability in the pathogenesis of autoimmune disease. Autoimmun Rev, 5, 299-305 (2006)
doi:10.1016/j.autrev.2005.10.013
36. Eberhardt, W., A. Doller, S. Akool el & J. Pfeilschifter: Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther, 114, 56-73 (2007)
doi:10.1016/j.pharmthera.2007.01.002
37. Katsanou, V., M. Dimitriou & D. L. Kontoyiannis: Post-transcriptional regulators in inflammation: exploring new avenues in biological therapeutics. Ernst Schering Found Symp Proc, 4, 37-57 (2006)
38. Cuenda, A. & S. Rousseau: p38 MAP-kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta, 1773, 1358-75 (2007)
doi:10.1016/j.bbamcr.2007.03.010
39. Ashwell, J. D.: The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol, 6, 532-40 (2006)
doi:10.1038/nri1865
40. Bain, J., H. McLauchlan, M. Elliott & P. Cohen: The specificities of protein kinase inhibitors: an update. Biochemical Journal, 371, 199-204 (2003)
doi:10.1042/BJ20021535
41. Kuma, Y., G. Sabio, J. Bain, N. Shpiro, R. Marquez & A. Cuenda: BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo. Journal of Biological Chemistry, 280, 19472-9 (2005)
doi:10.1074/jbc.M414221200
42. Saklatvala, J.: The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol, 4, 372-7 (2004)
doi:10.1016/j.coph.2004.03.009
43. Schindler, J. F., J. B. Monahan & W. G. Smith: p38 pathway kinases as anti-inflammatory drug targets. J Dent Res, 86, 800-11 (2007)
44. Goldstein, D. M. & T. Gabriel: Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr Top Med Chem, 5, 1017-29 (2005)
doi:10.2174/1568026054985939
45. Keren, A., Y. Tamir & E. Bengal: The p38 MAPK signaling pathway: a major regulator of skeletal muscle development. Mol Cell Endocrinol, 252, 224-30 (2006)
doi:10.1016/j.mce.2006.03.017
46. Lluis, F., E. Perdiguero, A. R. Nebreda & P. Munoz-Canoves: Regulation of skeletal muscle gene expression by p38 MAP kinases. Trends in Cell Biology, 16, 36-44 (2006)
doi:10.1016/j.tcb.2005.11.002
47. Dambach, D. M.: Potential adverse effects associated with inhibition of p38alpha/beta MAP kinases. Curr Top Med Chem, 5, 929-39 (2005)
doi:10.2174/1568026054985911
48. Prichett, W., A. Hand, J. Sheilds & D. Dunnington: Mechanism of action of bicyclic imidazoles defines a translational regulatory pathway for tumor necrosis factor alpha. J Inflamm, 45, 97-105 (1995)
49. Young, P., P. McDonnell, D. Dunnington, A. Hand, J. Laydon & J. Lee: Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents & Actions, 39 Spec No, C67-9 (1993)
50. Brook, M., G. Sully, A. R. Clark & J. Saklatvala: Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Letters, 483, 57-61 (2000)
doi:10.1016/S0014-5793(00)02084-6
51. Smith, S. J., P. S. Fenwick, A. G. Nicholson, F. Kirschenbaum, T. K. Finney-Hayward, L. S. Higgins, M. A. Giembycz, P. J. Barnes & L. E. Donnelly: Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol, 149, 393-404 (2006)
doi:10.1038/sj.bjp.0706885
52. Rutault, K., C. A. Hazzalin & L. C. Mahadevan: Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha (TNF-alpha) mRNA induction. Evidence for selective destabilization of TNF-alpha transcripts. Journal of Biological Chemistry, 276, 6666-74. (2001)
doi:10.1074/jbc.M005486200
53. Thuraisingam, T., Y. Z. Xu, J. Moisan, C. Lachance, J. Garnon, S. Di Marco, M. Gaestel & D. Radzioch: Distinct role of MAPKAPK-2 in the regulation of TNF gene expression by Toll-like receptor 7 and 9 ligands. Molecular Immunology, 44, 3482-91 (2007)
doi:10.1016/j.molimm.2007.03.019
54. Chung, Y. J., H. R. Zhou & J. J. Pestka: Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-alpha expression by deoxynivalenol (vomitoxin). Toxicol Appl Pharmacol, 193, 188-201 (2003)
doi:10.1016/S0041-008X(03)00299-0
55. Rajasingh, J., E. Bord, C. Luedemann, J. Asai, H. Hamada, T. Thorne, G. Qin, D. Goukassian, Y. Zhu, D. W. Losordo & R. Kishore: IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression. FASEB Journal, 20, 2112-4 (2006)
doi:10.1096/fj.06-6084fje
56. Marchant, A., C. Gueydan, L. Houzet, Z. Amraoui, A. Sels, G. Huez, M. Goldman & V. Kruys: Defective translation of tumor necrosis factor mRNA in lipopolysaccharide-tolerant macrophages. J Inflamm, 46, 114-23 (1996)
57. Abraham, S. M., T. Lawrence, A. Kleiman, P. Warden, M. Medghalchi, J. Tuckermann, J. Saklatvala & A. R. Clark: Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. Journal of Experimental Medicine, 203, 1883-9 (2006)
doi:10.1084/jem.20060336
58. Han, J. H., B. Beutler & G. Huez: Complex regulation of tumor necrosis factor mRNA turnover in lipopolysaccharide-activated macrophages. Biochimica et Biophysica Acta, 1090, 22-8 (1991)
59. Kruys, V., K. Kemmer, A. Shakhov, V. Jongeneel & B. Beutler: Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect. Proceedings of the National Academy of Sciences of the United States of America, 89, 673-7 (1992)
doi:10.1073/pnas.89.2.673
60. MacKenzie, S., N. Fernandez-Troy & E. Espel: Post-transcriptional regulation of TNF-alpha during in vitro differentiation of human monocytes/macrophages in primary culture. Journal of Leukocyte Biology, 71, 1026-32 (2002)
61. Kontoyiannis, D., A. Kotlyarov, E. Carballo, L. Alexopoulou, P. J. Blackshear, M. Gaestel, R. Davis, R. Flavell & G. Kollias: Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. EMBO Journal, 20, 3760-70 (2001)
doi:10.1093/emboj/20.14.3760
62. Piecyk, M., S. Wax, A. R. Beck, N. Kedersha, M. Gupta, B. Maritim, S. Chen, C. Gueydan, V. Kruys, M. Streuli & P. Anderson: TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha. EMBO Journal, 19, 4154-63. (2000)
doi:10.1093/emboj/19.15.4154
63. Raabe, T., M. Bukrinsky & R. A. Currie: Relative contribution of transcription and translation to the induction of tumor necrosis factor-alpha by lipopolysaccharide. Journal of Biological Chemistry, 273, 974-80 (1998)
doi:10.1074/jbc.273.2.974
64. Garnon, J., C. Lachance, S. Di Marco, Z. Hel, D. Marion, M. C. Ruiz, M. M. Newkirk, E. W. Khandjian & D. Radzioch: Fragile X-related protein FXR1P regulates proinflammatory cytokine tumor necrosis factor expression at the post-transcriptional level. Journal of Biological Chemistry, 280, 5750-63 (2005)
doi:10.1074/jbc.M401988200
65. Gueydan, C., L. Droogmans, P. Chalon, G. Huez, D. Caput & V. Kruys: Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA. Journal of Biological Chemistry, 274, 2322-6 (1999)
doi:10.1074/jbc.274.4.2322
66. Xu, N., P. Loflin, C. Y. Chen & A. B. Shyu: A broader role for AU-rich element-mediated mRNA turnover revealed by a new transcriptional pulse strategy. Nucleic Acids Research, 26, 558-65 (1998)
doi:10.1093/nar/26.2.558
67. Dean, J. L., S. J. Sarsfield, E. Tsounakou & J. Saklatvala: p38 Mitogen-activated protein kinase stabilizes mRNAs that contain cyclooxygenase-2 and tumor necrosis factor AU-rich elements by inhibiting deadenylation. Journal of Biological Chemistry, 278, 39470-6 (2003)
doi:10.1074/jbc.M306345200
68. Goedert, M., A. Cuenda, M. Craxton, R. Jakes & P. Cohen: Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO Journal, 16, 3563-71 (1997)
doi:10.1093/emboj/16.12.3563
69. Cuenda, A., P. Cohen, V. Buee-Scherrer & M. Goedert: Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO Journal, 16, 295-305 (1997)
doi:10.1093/emboj/16.2.295
70. Gaestel, M.: MAPKAP kinases - MKs - two's company, three's a crowd. Nat Rev Mol Cell Biol, 7, 120-30 (2006)
doi:10.1038/nrm1834
71. Kotlyarov, A. & M. Gaestel: Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? Biochem Soc Trans, 30, 959-63 (2002)
doi:10.1042/BST0300959
72. Winzen, R., M. Kracht, B. Ritter, A. Wilhelm, C. Y. Chen, A. B. Shyu, M. Muller, M. Gaestel, K. Resch & H. Holtmann: The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO Journal, 18, 4969-80 (1999)
doi:10.1093/emboj/18.18.4969
73. Mavropoulos, A., G. Sully, A. P. Cope & A. R. Clark: Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells. Blood, 105, 282-8 (2005)
doi:10.1182/blood-2004-07-2782
74. Tchen, C. R., M. Brook, J. Saklatvala & A. R. Clark: The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself. Journal of Biological Chemistry, 279, 32393-400 (2004)
doi:10.1074/jbc.M402059200
75. Lasa, M., K. R. Mahtani, A. Finch, G. Brewer, J. Saklatvala & A. R. Clark: Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Molecular & Cellular Biology, 20, 4265-74 (2000)
doi:10.1128/MCB.20.12.4265-4274.2000
76. Han, Q., J. Leng, D. Bian, C. Mahanivong, K. A. Carpenter, Z. K. Pan, J. Han & S. Huang: Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. Journal of Biological Chemistry, 277, 48379-85 (2002)
doi:10.1074/jbc.M209542200
77. Kotlyarov, A., A. Neininger, C. Schubert, R. Eckert, C. Birchmeier, H. D. Volk & M. Gaestel: MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nature Cell Biology, 1, 94-7 (1999)
doi:10.1038/10061
78. Ronkina, N., A. Kotlyarov, O. Dittrich-Breiholz, M. Kracht, E. Hitti, K. Milarski, R. Askew, S. Marusic, L. L. Lin, M. Gaestel & J. B. Telliez: The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK. Molecular & Cellular Biology, 27, 170-81 (2007)
doi:10.1128/MCB.01456-06
79. Neininger, A., D. Kontoyiannis, A. Kotlyarov, R. Winzen, R. Eckert, H. D. Volk, H. Holtmann, G. Kollias & M. Gaestel: MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. Journal of Biological Chemistry, 277, 3065-8 (2002)
doi:10.1074/jbc.C100685200
80. Wang, X., L. Xu, H. Wang, P. R. Young, M. Gaestel & G. Z. Feuerstein: Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 deficiency protects brain from ischemic injury in mice. Journal of Biological Chemistry, 277, 43968-72 (2002)
doi:10.1074/jbc.M206837200
81. Culbert, A. A., S. D. Skaper, D. R. Howlett, N. A. Evans, L. Facci, P. E. Soden, Z. M. Seymour, F. Guillot, M. Gaestel & J. C. Richardson: MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. Journal of Biological Chemistry, 281, 23658-67 (2006)
doi:10.1074/jbc.M513646200
82. Tietz, A. B., A. Malo, J. Diebold, A. Kotlyarov, A. Herbst, F. T. Kolligs, B. Brandt-Nedelev, W. Halangk, M. Gaestel, B. Goke & C. Schafer: Gene deletion of MK2 inhibits TNF-alpha and IL-6 and protects against cerulein-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol, 290, G1298-306 (2006)
doi:10.1152/ajpgi.00530.2005
83. Hegen, M., M. Gaestel, C. L. Nickerson-Nutter, L. L. Lin & J. B. Telliez: MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. Journal of Immunology, 177, 1913-7 (2006)
84. Hitti, E., T. Iakovleva, M. Brook, S. Deppenmeier, A. D. Gruber, D. Radzioch, A. R. Clark, P. J. Blackshear, A. Kotlyarov & M. Gaestel: Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Molecular & Cellular Biology, 26, 2399-407 (2006)
doi:10.1128/MCB.26.6.2399-2407.2006
85. Kontoyiannis, D., M. Pasparakis, T. T. Pizarro, F. Cominelli & G. Kollias: Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity, 10, 387-98 (1999)
doi:10.1016/S1074-7613(00)80038-2
86. Clark, A. R., J. L. Dean & J. Saklatvala: Post-transcriptional regulation of gene expression by mitogen-activated protein kinase p38. FEBS Letters, 546, 37-44 (2003)
doi:10.1016/S0014-5793(03)00439-3
87. Winzen, R., G. Gowrishankar, F. Bollig, N. Redich, K. Resch & H. Holtmann: Distinct domains of AU-rich elements exert different functions in mRNA destabilization and stabilization by p38 mitogen-activated protein kinase or HuR. Molecular & Cellular Biology, 24, 4835-47 (2004)
doi:10.1128/MCB.24.11.4835-4847.2004
88. Sully, G., J. L. Dean, R. Wait, L. Rawlinson, T. Santalucia, J. Saklatvala & A. R. Clark: Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 (AU-rich element/poly (U)-binding/degradation factor-1), AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1). Biochemical Journal, 377, 629-39 (2004)
doi:10.1042/BJ20031484
89. Rousseau, S., N. Morrice, M. Peggie, D. G. Campbell, M. Gaestel & P. Cohen: Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO Journal, 21, 6505-14. (2002)
doi:10.1093/emboj/cdf639
90. Numahata, K., T. Komagata, N. Hirasawa, K. Someya, Y. Q. Xiao & K. Ohuchi: Analysis of the mechanism regulating the stability of rat macrophage inflammatory protein-2 mRNA in RBL-2H3 cells. J Cell Biochem, 90, 976-86 (2003)
doi:10.1002/jcb.10710
91. Deleault, K. M., S. J. Skinner & S. A. Brooks: Tristetraprolin regulates TNF TNF-alpha mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. Molecular Immunology, 45, 13-24 (2008)
doi:10.1016/j.molimm.2007.05.017
92. Dumitru, C. D., J. D. Ceci, C. Tsatsanis, D. Kontoyiannis, K. Stamatakis, J. Lin, C. Patriotis, N. A. Jenkins, N. G. Copeland, G. Kollias & P. N. Tsichlis: TNF-alpha Induction by LPS Is Regulated Posttranscriptionally via a Tpl2/ERK-Dependent Pathway. Cell1071-1083 (2000)
doi:10.1016/S0092-8674(00)00210-5
93. Skinner, S. J., K. M. Deleault, R. Fecteau & S. A. Brooks: Extracellular signal-regulated kinase regulation of tumor necrosis factor-alpha mRNA nucleocytoplasmic transport requires TAP/NxT1 binding and the AU-Rich element. Journal of Biological Chemistry (2007)
94. Phelps, M., A. Phillips, M. Darley & J. P. Blaydes: MEK-ERK signaling controls Hdm2 oncoprotein expression by regulating hdm2 mRNA export to the cytoplasm. Journal of Biological Chemistry, 280, 16651-8 (2005)
doi:10.1074/jbc.M412334200
95. Swantek, J. L., M. H. Cobb & T. D. Geppert: Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Molecular & Cellular Biology, 17, 6274-82 (1997)
96. Lasa, M., S. M. Abraham, C. Boucheron, J. Saklatvala & A. R. Clark: Dexamethasone causes sustained expression of mitogen-activated protein kinase (MAPK) phosphatase 1 and phosphatase-mediated inhibition of MAPK p38. Molecular & Cellular Biology, 22, 7802-11. (2002)
doi:10.1128/MCB.22.22.7802-7811.2002
97. Chen, P., J. Li, J. Barnes, G. C. Kokkonen, J. C. Lee & Y. Liu: Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. Journal of Immunology, 169, 6408-16. (2002)
98. Chen, C. Y., F. Del Gatto-Konczak, Z. Wu & M. Karin: Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science, 280, 1945-9. (1998)
doi:10.1126/science.280.5371.1945
99. Chen, C. Y., R. Gherzi, J. S. Andersen, G. Gaietta, K. Jurchott, H. D. Royer, M. Mann & M. Karin: Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Genes & Development, 14, 1236-48. (2000)
100. Lo, S. J., C. C. Lee & H. J. Lai: The nucleolus: reviewing oldies to have new understandings. Cell Res, 16, 530-8 (2006)
doi:10.1038/sj.cr.7310070
101. Kohno, K., H. Izumi, T. Uchiumi, M. Ashizuka & M. Kuwano: The pleiotropic functions of the Y-box-binding protein, YB-1. Bioessays, 25, 691-8 (2003)
doi:10.1002/bies.10300
102. Fukunaga, R. & T. Hunter: MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO Journal, 16, 1921-33 (1997)
doi:10.1093/emboj/16.8.1921
103. Waskiewicz, A. J., A. Flynn, C. G. Proud & J. A. Cooper: Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO Journal, 16, 1909-20 (1997)
doi:10.1093/emboj/16.8.1909
104. Buxade, M., J. L. Parra, S. Rousseau, N. Shpiro, R. Marquez, N. Morrice, J. Bain, E. Espel & C. G. Proud: The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity, 23, 177-89 (2005)
doi:10.1016/j.immuni.2005.06.009
105. Buxade, M., N. Morrice, D. L. Krebs & C. G. Proud: The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. Journal of Biological Chemistry, 283, 57-65 (2008)
doi:10.1074/jbc.M705286200
106. Andersson, K. & R. Sundler: Posttranscriptional regulation of TNFalpha expression via eukaryotic initiation factor 4E (eIF4E) phosphorylation in mouse macrophages. Cytokine, 33, 52-7 (2006)
doi:10.1016/j.cyto.2005.11.017
107. Kjellerup, R. B., K. Kragballe, L. Iversen & C. Johansen: Pro-inflammatory cytokine release in keratinocytes is mediated through the MAPK signal-integrating kinases. Exp Dermatol (2007)
108. Rowlett, R. M., C. A. Chrestensen, M. Nyce, M. G. Harp, J. W. Pelo, F. Cominelli, P. B. Ernst, T. T. Pizarro, T. W. Sturgill & M. T. Worthington: MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. Am J Physiol Gastrointest Liver Physiol, 294, G452-9 (2008)
doi:10.1152/ajpgi.00077.2007
109. Ueda, T., R. Watanabe-Fukunaga, H. Fukuyama, S. Nagata & R. Fukunaga: Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Molecular & Cellular Biology, 24, 6539-49 (2004)
doi:10.1128/MCB.24.15.6539-6549.2004
110. Carrick, D. M., W. S. Lai & P. J. Blackshear: The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis. Arthritis Res Ther, 6, 248-64 (2004)
doi:10.1186/ar1441
111. Brook, M., C. R. Tchen, T. Santalucia, J. McIlrath, J. S. Arthur, J. Saklatvala & A. R. Clark: Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Molecular & Cellular Biology, 26, 2408-18 (2006)
doi:10.1128/MCB.26.6.2408-2418.2006
112. Mahtani, K. R., M. Brook, J. L. Dean, G. Sully, J. Saklatvala & A. R. Clark: Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Molecular & Cellular Biology, 21, 6461-9. (2001)
doi:10.1128/MCB.21.9.6461-6469.2001
113. Brooks, S. A., J. E. Connolly & W. F. Rigby: The role of mRNA turnover in the regulation of tristetraprolin expression: evidence for an extracellular signal-regulated kinase-specific, AU-rich element-dependent, autoregulatory pathway. Journal of Immunology, 172, 7263-71 (2004)
114. Lai, W. S., J. S. Parker, S. F. Grissom, D. J. Stumpo & P. J. Blackshear: Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts. Molecular & Cellular Biology, 26, 9196-208 (2006)
doi:10.1128/MCB.00945-06
115. Raghavan, A., R. L. Robison, J. McNabb, C. R. Miller, D. A. Williams & P. R. Bohjanen: HuA and tristetraprolin are induced following T cell activation and display distinct but overlapping RNA binding specificities. Journal of Biological Chemistry, 276, 47958-65 (2001)
116. Ogilvie, R. L., M. Abelson, H. H. Hau, I. Vlasova, P. J. Blackshear & P. R. Bohjanen: Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. Journal of Immunology, 174, 953-61 (2005)
117. Frasca, D., A. M. Landin, J. P. Alvarez, P. J. Blackshear, R. L. Riley & B. B. Blomberg: Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of E47 mRNA. Journal of Immunology, 179, 918-27 (2007)
118. Dean, J. L., G. Sully, A. R. Clark & J. Saklatvala: The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation. Cell Signal, 16, 1113-21 (2004)
doi:10.1016/j.cellsig.2004.04.006
119. Carrick, D. M. & P. J. Blackshear: Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines. Archives of Biochemistry & Biophysics, 462, 278-85 (2007)
doi:10.1016/j.abb.2007.04.011
120. Lai, W. S., E. Carballo, J. M. Thorn, E. A. Kennington & P. J. Blackshear: Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA. Journal of Biological Chemistry, 275, 17827-37 (2000)
doi:10.1074/jbc.M001696200
121. Lai, W. S. & P. J. Blackshear: Interactions of CCCH zinc finger proteins with mRNA: tristetraprolin-mediated AU-rich element-dependent mRNA degradation can occur in the absence of a poly (A) tail. Journal of Biological Chemistry, 276, 23144-54 (2001)
doi:10.1074/jbc.M100680200
122. Stumpo, D. J., N. A. Byrd, R. S. Phillips, S. Ghosh, R. R. Maronpot, T. Castranio, E. N. Meyers, Y. Mishina & P. J. Blackshear: Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family. Molecular & Cellular Biology, 24, 6445-55 (2004)
doi:10.1128/MCB.24.14.6445-6455.2004
123. Bell, S. E., M. J. Sanchez, O. Spasic-Boskovic, T. Santalucia, L. Gambardella, G. J. Burton, J. J. Murphy, J. D. Norton, A. R. Clark & M. Turner: The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expression. Dev Dyn, 235, 3144-55 (2006)
doi:10.1002/dvdy.20949
124. Ramos, S. B., D. J. Stumpo, E. A. Kennington, R. S. Phillips, C. B. Bock, F. Ribeiro-Neto & P. J. Blackshear: The CCCH tandem zinc-finger protein Zfp36l2 is crucial for female fertility and early embryonic development. Development, 131, 4883-93 (2004)
doi:10.1242/dev.01336
125. Blackshear, P. J., W. S. Lai, E. A. Kennington, G. Brewer, G. M. Wilson, X. Guan & P. Zhou: Characteristics of the interaction of a synthetic human tristetraprolin tandem zinc finger peptide with AU-rich element-containing RNA substrates. Journal of Biological Chemistry, 278, 19947-55 (2003)
doi:10.1074/jbc.M301290200
126. Brewer, B. Y., J. Malicka, P. J. Blackshear & G. M. Wilson: RNA sequence elements required for high affinity binding by the zinc finger domain of tristetraprolin: conformational changes coupled to the bipartite nature of Au-rich MRNA-destabilizing motifs. Journal of Biological Chemistry, 279, 27870-7 (2004)
doi:10.1074/jbc.M402551200
127. Worthington, M. T., J. W. Pelo, M. A. Sachedina, J. L. Applegate, K. O. Arseneau & T. T. Pizarro: RNA binding properties of the AU-rich element-binding recombinant Nup475/TIS11/tristetraprolin protein. Journal of Biological Chemistry, 277, 48558-64. (2002)
doi:10.1074/jbc.M206505200
128. Stoecklin, G., S. A. Tenenbaum, T. Mayo, S. V. Chittur, A. D. George, T. E. Baroni, P. J. Blackshear & P. Anderson: Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. Journal of Biological Chemistry (2008)
129. Hudson, B. P., M. A. Martinez-Yamout, H. J. Dyson & P. E. Wright: Recognition of the mRNA AU-rich element by the zinc finger domain of TIS11d. Nat Struct Mol Biol, 11, 257-64 (2004)
doi:10.1038/nsmb738
130. Brewer, B. Y., J. D. Ballin, E. J. Fialcowitz-White, P. J. Blackshear & G. M. Wilson: Substrate dependence of conformational changes in the RNA-binding domain of tristetraprolin assessed by fluorescence spectroscopy of tryptophan mutants. Biochemistry, 45, 13807-17 (2006)
doi:10.1021/bi061320j
131. Taylor, G. A., M. J. Thompson, W. S. Lai & P. J. Blackshear: Mitogens stimulate the rapid nuclear to cytosolic translocation of tristetraprolin, a potential zinc-finger transcription factor. Mol Endocrinol, 10, 140-6 (1996)
doi:10.1210/me.10.2.140
132. Phillips, R. S., S. B. Ramos & P. J. Blackshear: Members of the tristetraprolin family of tandem CCCH zinc finger proteins exhibit CRM1-dependent nucleocytoplasmic shuttling. Journal of Biological Chemistry, 277, 11606-13. (2002)
doi:10.1074/jbc.M111457200
133. Carman, J. A. & S. G. Nadler: Direct association of tristetraprolin with the nucleoporin CAN/Nup214. Biochemical & Biophysical Research Communications, 315, 445-9 (2004)
doi:10.1016/j.bbrc.2004.01.080
134. Murata, T., Y. Yoshino, N. Morita & N. Kaneda: Identification of nuclear import and export signals within the structure of the zinc finger protein TIS11. Biochemical & Biophysical Research Communications, 293, 1242-7 (2002)
doi:10.1016/S0006-291X(02)00363-7
135. Johnson, B. A., J. R. Stehn, M. B. Yaffe & T. K. Blackwell: Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms. Journal of Biological Chemistry, 277, 18029-36. (2002)
doi:10.1074/jbc.M110465200
136. Mackintosh, C.: Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes. Biochemical Journal, 381, 329-42 (2004)
doi:10.1042/BJ20031332
137. Porter, G. W., F. R. Khuri & H. Fu: Dynamic 14-3-3/client protein interactions integrate survival and apoptotic pathways. Semin Cancer Biol, 16, 193-202 (2006)
doi:10.1016/j.semcancer.2006.03.003
138. Aitken, A.: 14-3-3 proteins: a historic overview. Semin Cancer Biol, 16, 162-72 (2006)
doi:10.1016/j.semcancer.2006.03.005
139. Lai, W. S., E. Carballo, J. R. Strum, E. A. Kennington, R. S. Phillips & P. J. Blackshear: Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Molecular & Cellular Biology, 19, 4311-23 (1999)
140. Carballo, E., W. S. Lai & P. J. Blackshear: Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood, 95, 1891-9 (2000)
141. Lai, W. S., D. M. Carrick & P. J. Blackshear: Influence of nonameric AU-rich tristetraprolin binding sites on mRNA deadenylation and turnover. Journal of Biological Chemistry (2005)
142. Taylor, G. A., E. Carballo, D. M. Lee, W. S. Lai, M. J. Thompson, D. D. Patel, D. I. Schenkman, G. S. Gilkeson, H. E. Broxmeyer, B. F. Haynes & P. J. Blackshear: A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity, 4, 445-54 (1996)
doi:10.1016/S1074-7613(00)80411-2
143. Carballo, E., G. S. Gilkeson & P. J. Blackshear: Bone marrow transplantation reproduces the tristetraprolin-deficiency syndrome in recombination activating gene-2 (-/-) mice. Evidence that monocyte/macrophage progenitors may be responsible for TNFalpha overproduction. Journal of Clinical Investigation, 100, 986-95 (1997)
doi:10.1172/JCI119649
144. Carballo, E., W. S. Lai & P. J. Blackshear: Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science, 281, 1001-5 (1998)
doi:10.1126/science.281.5379.1001
145. Phillips, K., N. Kedersha, L. Shen, P. J. Blackshear & P. Anderson: Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor {alpha}, cyclooxygenase 2, and inflammatory arthritis. Proceedings of the National Academy of Sciences of the United States of America, 101, 2011-2016 (2004)
doi:10.1073/pnas.0400148101
146. Datta, S., R. Biswas, M. Novotny, P. G. Pavicic, Jr., T. Herjan, P. Mandal & T. A. Hamilton: Tristetraprolin Regulates CXCL1 (KC) mRNA Stability. Journal of Immunology, 180, 2545-52 (2008)
147. Taylor, G. A., M. J. Thompson, W. S. Lai & P. J. Blackshear: Phosphorylation of tristetraprolin, a potential zinc finger transcription factor, by mitogen stimulation in intact cells and by mitogen-activated protein kinase in vitro. Journal of Biological Chemistry, 270, 13341-7 (1995)
doi:10.1074/jbc.270.22.13341
148. Cao, H., J. S. Tuttle & P. J. Blackshear: Immunological characterization of tristetraprolin as a low abundance, inducible, stable cytosolic protein. Journal of Biological Chemistry, 279, 21489-99 (2004)
doi:10.1074/jbc.M400900200
149. Cao, H., L. J. Deterding, J. D. Venable, E. A. Kennington, J. R. Yates, 3rd, K. B. Tomer & P. J. Blackshear: Identification of the anti-inflammatory protein tristetraprolin as a hyperphosphorylated protein by mass spectrometry and site-directed mutagenesis. Biochemical Journal, 394, 285-97 (2006)
doi:10.1042/BJ20051316
150. Carballo, E., H. Cao, W. S. Lai, E. A. Kennington, D. Campbell & P. J. Blackshear: Decreased sensitivity of tristetraprolin-deficient cells to p38 inhibitors suggests the involvement of tristetraprolin in the p38 signaling pathway. Journal of Biological Chemistry, 276, 42580-7 (2001)
doi:10.1074/jbc.M104953200
151. Zhu, W., M. A. Brauchle, F. Di Padova, H. Gram, L. New, K. Ono, J. S. Downey & J. Han: Gene suppression by tristetraprolin and release by the p38 pathway. Am J Physiol Lung Cell Mol Physiol, 281, L499-508. (2001)
152. Cao, H., F. Dzineku & P. J. Blackshear: Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases. Archives of Biochemistry & Biophysics, 412, 106-120. (2003)
doi:10.1016/S0003-9861(03)00012-2
153. Cao, H.: Expression, purification, and biochemical characterization of the antiinflammatory tristetraprolin: a zinc-dependent mRNA binding protein affected by posttranslational modifications. Biochemistry, 43, 13724-38 (2004)
doi:10.1021/bi049014y
154. Cao, H., L. J. Deterding & P. J. Blackshear: Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin. Expert Rev Proteomics, 4, 711-26 (2007)
doi:10.1586/14789450.4.6.711
155. Chrestensen, C. A., M. J. Schroeder, J. Shabanowitz, D. F. Hunt, J. W. Pelo, M. T. Worthington & T. W. Sturgill: MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. Journal of Biological Chemistry, 279, 10176-84 (2004)
doi:10.1074/jbc.M310486200
156. Sun, L., G. Stoecklin, S. Van Way, V. Hinkovska-Galcheva, R. F. Guo, P. Anderson & T. P. Shanley: Tristetraprolin (TTP)-14-3-3 complex formation protects TTP from dephosphorylation by protein phosphatase 2a and stabilizes tumor necrosis factor-alpha mRNA. Journal of Biological Chemistry, 282, 3766-77 (2007)
doi:10.1074/jbc.M607347200
157. Benjamin, D., M. Schmidlin, L. Min, B. Gross & C. Moroni: BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites. Molecular & Cellular Biology, 26, 9497-507 (2006)
doi:10.1128/MCB.01099-06
158. Stoecklin, G., T. Stubbs, N. Kedersha, S. Wax, W. F. Rigby, T. K. Blackwell & P. Anderson: MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO Journal, 23, 1313-1324 (2004)
doi:10.1038/sj.emboj.7600163
159. Marderosian, M., A. Sharma, A. P. Funk, R. Vartanian, J. Masri, O. D. Jo & J. F. Gera: Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling. Oncogene, 25, 6277-90 (2006)
doi:10.1038/sj.onc.1209645
160. Kedersha, N. & P. Anderson: Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem Soc Trans, 30, 963-9 (2002)
doi:10.1042/BST0300963
161. Kedersha, N., G. Stoecklin, M. Ayodele, P. Yacono, J. Lykke-Andersen, M. J. Fitzler, D. Scheuner, R. J. Kaufman, D. E. Golan & P. Anderson: Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. Journal of Cell Biology, 169, 871-84 (2005)
doi:10.1083/jcb.200502088
162. Corcoran, J. A., W. L. Hsu & J. R. Smiley: Herpes simplex virus ICP27 is required for virus-induced stabilization of the ARE-containing IEX-1 mRNA encoded by the human IER3 gene. Journal of Virology, 80, 9720-9 (2006)
doi:10.1128/JVI.01216-06
163. Essafi-Benkhadir, K., C. Onesto, E. Stebe, C. Moroni & G. Pages: Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation. Molecular Biology of the Cell, 18, 4648-58 (2007)
doi:10.1091/mbc.E07-06-0570
164. Brennan, C. M. & J. A. Steitz: HuR and mRNA stability. Cell Mol Life Sci, 58, 266-77. (2001)
doi:10.1007/PL00000854
165. Lopez de Silanes, I., M. Zhan, A. Lal, X. Yang & M. Gorospe: Identification of a target RNA motif for RNA-binding protein HuR. Proceedings of the National Academy of Sciences of the United States of America, 101, 2987-92 (2004)
doi:10.1073/pnas.0306453101
166. Lopez de Silanes, I., J. Fan, C. J. Galban, R. G. Spencer, K. G. Becker & M. Gorospe: Global analysis of HuR-regulated gene expression in colon cancer systems of reducing complexity. Gene Expr, 12, 49-59 (2004)
167. Lopez de Silanes, I., A. Lal & M. Gorospe: HuR: post-transcriptional paths to malignancy. RNA Biol, 2, 11-3 (2005)
168. Abdelmohsen, K., A. Lal, H. H. Kim & M. Gorospe: Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle, 6, 1288-92 (2007)
169. Dixon, D. A., N. D. Tolley, P. H. King, L. B. Nabors, T. M. McIntyre, G. A. Zimmerman & S. M. Prescott: Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. Journal of Clinical Investigation, 108, 1657-65. (2001)
170. Lopez de Silanes, I., J. Fan, X. Yang, A. B. Zonderman, O. Potapova, E. S. Pizer & M. Gorospe: Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene, 22, 7146-54 (2003)
doi:10.1038/sj.onc.1206862
171. Jin, S. H., T. I. Kim, K. M. Yang & W. H. Kim: Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR. Eur J Pharmacol, 558, 14-20 (2007)
doi:10.1016/j.ejphar.2006.11.060
172. Li, B., J. Si & J. W. Dewille: Ultraviolet radiation (UVR) activates p38 MAP kinase and induces post-transcriptional stabilization of the C/EBPdelta mRNA in G (0) growth arrested mammary epithelial cells. J Cell Biochem (2007)
173. Lin, F. Y., Y. H. Chen, Y. W. Lin, J. S. Tsai, J. W. Chen, H. J. Wang, Y. L. Chen, C. Y. Li & S. J. Lin: The role of human antigen R, an RNA-binding protein, in mediating the stabilization of toll-like receptor 4 mRNA induced by endotoxin: a novel mechanism involved in vascular inflammation. Arterioscler Thromb Vasc Biol, 26, 2622-9 (2006)
doi:10.1161/01.ATV.0000246779.78003.cf
174. Song, I. S., S. Tatebe, W. Dai & M. T. Kuo: Delayed mechanism for induction of gamma-glutamylcysteine synthetase heavy subunit mRNA stability by oxidative stress involving p38 mitogen-activated protein kinase signaling. Journal of Biological Chemistry, 280, 28230-40 (2005)
doi:10.1074/jbc.M413103200
175. Subbaramaiah, K., T. P. Marmo, D. A. Dixon & A. J. Dannenberg: Regulation of cyclooxgenase-2 mRNA stability by taxanes: evidence for involvement of p38, MAPKAPK-2, and HuR. Journal of Biological Chemistry, 278, 37637-47 (2003)
doi:10.1074/jbc.M301481200
176. Tran, H., F. Maurer & Y. Nagamine: Stabilization of urokinase and urokinase receptor mRNAs by HuR is linked to its cytoplasmic accumulation induced by activated mitogen-activated protein kinase-activated protein kinase 2. Molecular & Cellular Biology, 23, 7177-88 (2003)
doi:10.1128/MCB.23.20.7177-7188.2003
177. Ford, L. P., J. Watson, J. D. Keene & J. Wilusz: ELAV proteins stabilize deadenylated intermediates in a novel in vitro mRNA deadenylation/degradation system. Genes And Development, 13, 188-201 (1999)
doi:10.1101/gad.13.2.188
178. Peng, S. S., C. Y. Chen, N. Xu & A. B. Shyu: RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO Journal, 17, 3461-70 (1998)
doi:10.1093/emboj/17.12.3461
179. Seko, Y., H. Azmi, R. Fariss & J. A. Ragheb: Selective cytoplasmic translocation of HuR and site-specific binding to the interleukin-2 mRNA are not sufficient for CD28-mediated stabilization of the mRNA. Journal of Biological Chemistry, 279, 33359-67 (2004)
doi:10.1074/jbc.M312306200
180. Wang, W., X. Yang, T. Kawai, I. Lopez de Silanes, K. Mazan-Mamczarz, P. Chen, Y. M. Chook, C. Quensel, M. Kohler & M. Gorospe: AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR. Journal of Biological Chemistry, 279, 48376-88 (2004)
doi:10.1074/jbc.M409014200
181. Abdelmohsen, K., R. Pullmann, Jr., A. Lal, H. H. Kim, S. Galban, X. Yang, J. D. Blethrow, M. Walker, J. Shubert, D. A. Gillespie, H. Furneaux & M. Gorospe: Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Molecular Cell, 25, 543-57 (2007)
doi:10.1016/j.molcel.2007.01.011
182. Doller, A., A. Huwiler, R. Muller, H. H. Radeke, J. Pfeilschifter & W. Eberhardt: Protein kinase C alpha-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2. Molecular Biology of the Cell, 18, 2137-48 (2007)
doi:10.1091/mbc.E06-09-0850
183. Zou, T., L. Liu, J. N. Rao, B. S. Marasa, J. Chen, L. Xiao, H. Zhou, M. Gorospe & J. Y. Wang: Polyamines modulate the subcellular localization of RNA-binding protein HuR through AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1. Biochemical Journal, 409, 389-98 (2008)
doi:10.1042/BJ20070860
184. Ruggiero, T., M. Trabucchi, M. Ponassi, G. Corte, C. Y. Chen, L. al-Haj, K. S. Khabar, P. Briata & R. Gherzi: Identification of a set of KSRP target transcripts upregulated by PI3K-AKT signaling. BMC Mol Biol, 8, 28 (2007)
doi:10.1186/1471-2199-8-28
185. Gherzi, R., M. Trabucchi, M. Ponassi, T. Ruggiero, G. Corte, C. Moroni, C. Y. Chen, K. S. Khabar, J. S. Andersen & P. Briata: The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling. PLoS Biol, 5, e5 (2006)
doi:10.1371/journal.pbio.0050005
186. Briata, P., S. V. Forcales, M. Ponassi, G. Corte, C. Y. Chen, M. Karin, P. L. Puri & R. Gherzi: p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Molecular Cell, 20, 891-903 (2005)
doi:10.1016/j.molcel.2005.10.021
187. Winzen, R., B. K. Thakur, O. Dittrich-Breiholz, M. Shah, N. Redich, S. Dhamija, M. Kracht & H. Holtmann: Functional analysis of KSRP interaction with the AU-rich element of interleukin-8 and identification of inflammatory mRNA targets. Molecular & Cellular Biology, 27, 8388-400 (2007)
doi:10.1128/MCB.01493-07
188. Garcia-Mayoral, M. F., D. Hollingworth, L. Masino, I. Diaz-Moreno, G. Kelly, R. Gherzi, C. F. Chou, C. Y. Chen & A. Ramos: The structure of the C-terminal KH domains of KSRP reveals a noncanonical motif important for mRNA degradation. Structure, 15, 485-98 (2007)
doi:10.1016/j.str.2007.03.006
189. Zhang, W., B. J. Wagner, K. Ehrenman, A. W. Schaefer, C. T. DeMaria, D. Crater, K. DeHaven, L. Long & G. Brewer: Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1. Molecular And Cellular Biology, 13, 7652-65 (1993)
190. Lu, J. Y., N. Sadri & R. J. Schneider: Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs. Genes & Development, 20, 3174-84 (2006)
doi:10.1101/gad.1467606
191. Sarkar, B., Q. Xi, C. He & R. J. Schneider: Selective degradation of AU-rich mRNAs promoted by the p37 AUF1 protein isoform. Molecular & Cellular Biology, 23, 6685-93 (2003)
doi:10.1128/MCB.23.18.6685-6693.2003
192. Shen, Z. J., S. Esnault & J. S. Malter: The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat Immunol, 6, 1280-7 (2005)
doi:10.1038/ni1266
193. Xu, N., C. Y. Chen & A. B. Shyu: Versatile role for hnRNP D isoforms in the differential regulation of cytoplasmic mRNA turnover. Molecular & Cellular Biology, 21, 6960-71 (2001)
doi:10.1128/MCB.21.20.6960-6971.2001
194. He, C. & R. Schneider: 14-3-3sigma is a p37 AUF1-binding protein that facilitates AUF1 transport and AU-rich mRNA decay. EMBO Journal, 25, 3823-31 (2006)
doi:10.1038/sj.emboj.7601264
195. Raineri, I., D. Wegmueller, B. Gross, U. Certa & C. Moroni: Roles of AUF1 isoforms, HuR and BRF1 in ARE-dependent mRNA turnover studied by RNA interference. Nucleic Acids Research, 32, 1279-88 (2004)
doi:10.1093/nar/gkh282
196. Dean, J. L., G. Sully, R. Wait, L. Rawlinson, A. R. Clark & J. Saklatvala: Identification of a novel AU-rich-element-binding protein which is related to AUF1. Biochemical Journal, 366, 709-19. (2002)
197. Lu, K. P. & X. Z. Zhou: The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol, 8, 904-16 (2007)
doi:10.1038/nrm2261
198. Takahashi, K., C. Uchida, R. W. Shin, K. Shimazaki & T. Uchida: Prolyl isomerase, Pin1: new findings of post-translational modifications and physiological substrates in cancer, asthma and Alzheimer's disease. Cell Mol Life Sci (2007)
199. Esnault, S., Z. J. Shen, E. Whitesel & J. S. Malter: The peptidyl-prolyl isomerase Pin1 regulates granulocyte-macrophage colony-stimulating factor mRNA stability in T lymphocytes. Journal of Immunology, 177, 6999-7006 (2006)
200. Esnault, S. & J. S. Malter: Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. Blood, 99, 4048-52. (2002)
doi:10.1182/blood.V99.11.4048
201. Wilson, G. M., J. Lu, K. Sutphen, Y. Suarez, S. Sinha, B. Brewer, E. C. Villanueva-Feliciano, R. M. Ysla, S. Charles & G. Brewer: Phosphorylation of p40AUF1 regulates binding to A + U-rich mRNA-destabilizing elements and protein-induced changes in ribonucleoprotein structure. Journal of Biological Chemistry, 278, 33039-48 (2003)
doi:10.1074/jbc.M305775200
202. Wilson, G. M., J. Lu, K. Sutphen, Y. Sun, Y. Huynh & G. Brewer: Regulation of A + U-rich element-directed mRNA turnover involving reversible phosphorylation of AUF1. Journal of Biological Chemistry, 278, 33029-38 (2003)
doi:10.1074/jbc.M305772200
203. Bollig, F., R. Winzen, M. Gaestel, S. Kostka, K. Resch & H. Holtmann: Affinity purification of ARE-binding proteins identifies poly (A)-binding protein 1 as a potential substrate in MK2-induced mRNA stabilization. Biochemical & Biophysical Research Communications, 301, 665-70. (2003)
doi:10.1016/S0006-291X(03)00015-9
204. Shyu, A. B., M. F. Wilkinson & A. van Hoof: Messenger RNA regulation: to translate or to degrade. EMBO Journal, 27, 471-81 (2008)
doi:10.1038/sj.emboj.7601977
205. Lodish, H. F., B. Zhou, G. Liu & C. Z. Chen: Micromanagement of the immune system by microRNAs. Nat Rev Immunol, 8, 120-30 (2008)
doi:10.1038/nri2252
206. Kato, M. & F. J. Slack: microRNAs: small molecules with big roles - C. elegans to human cancer. Biol Cell, 100, 71-81 (2008)
doi:10.1042/BC20070078
207. Filipowicz, W., S. N. Bhattacharyya & N. Sonenberg: Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet, 9, 102-14 (2008)
doi:10.1038/nrg2290
208. O'Connell, R. M., K. D. Taganov, M. P. Boldin, G. Cheng & D. Baltimore: MicroRNA-155 is induced during the macrophage inflammatory response. Proceedings of the National Academy of Sciences of the United States of America, 104, 1604-9 (2007)
doi:10.1073/pnas.0610731104
209. Yin, Q., X. Wang, J. McBride, C. Fewell & E. Flemington: B-cell receptor activation induces BIC/miR-155 expression through a conserved AP-1 element. Journal of Biological Chemistry, 283, 2654-62 (2008)
doi:10.1074/jbc.M708218200
210. Jing, Q., S. Huang, S. Guth, T. Zarubin, A. Motoyama, J. Chen, F. Di Padova, S. C. Lin, H. Gram & J. Han: Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell, 120, 623-34 (2005)
doi:10.1016/j.cell.2004.12.038
211. Fukui, N., Y. Ikeda, T. Ohnuki, A. Hikita, S. Tanaka, S. Yamane, R. Suzuki, L. J. Sandell & T. Ochi: Pro-inflammatory cytokine tumor necrosis factor-alpha induces bone morphogenetic protein-2 in chondrocytes via mRNA stabilization and transcriptional up-regulation. Journal of Biological Chemistry, 281, 27229-41 (2006)
doi:10.1074/jbc.M603385200
212. Sen, P., P. K. Chakraborty & S. Raha: p38 mitogen-activated protein kinase (p38MAPK) upregulates catalase levels in response to low dose H2O2 treatment through enhancement of mRNA stability. FEBS Letters, 579, 4402-6 (2005)
doi:10.1016/j.febslet.2005.06.081
213. Waterhouse, C. C., R. R. Joseph, G. L. Winsor, T. A. Lacombe & A. W. Stadnyk: Monocyte chemoattractant protein-1 production by intestinal epithelial cells in vitro: a role for p38 in epithelial chemokine expression. Journal of Interferon & Cytokine Research, 21, 223-30. (2001)
doi:10.1089/107999001750169853
214. Xiao, Y. Q., K. Someya, H. Morita, K. Takahashi & K. Ohuchi: Involvement of p38 MAPK and ERK/MAPK pathways in staurosporine-induced production of macrophage inflammatory protein-2 in rat peritoneal neutrophils. Biochimica et Biophysica Acta, 1450, 155-63 (1999)
doi:10.1016/S0167-4889(99)00042-7
215. Wang, S. W., J. Pawlowski, S. T. Wathen, S. D. Kinney, H. S. Lichenstein & C. L. Manthey: Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase. Inflamm Res, 48, 533-8 (1999)
doi:10.1007/s000110050499
216. Duque, J., M. D. Diaz-Munoz, M. Fresno & M. A. Iniguez: Up-regulation of cyclooxygenase-2 by interleukin-1beta in colon carcinoma cells. Cell Signal, 18, 1262-9 (2006)
doi:10.1016/j.cellsig.2005.10.009
217. Gauthier, M. L., C. R. Pickering, C. J. Miller, C. A. Fordyce, K. L. Chew, H. K. Berman & T. D. Tlsty: p38 regulates cyclooxygenase-2 in human mammary epithelial cells and is activated in premalignant tissue. Cancer Research, 65, 1792-9 (2005)
doi:10.1158/0008-5472.CAN-04-3507
218. Tessner, T. G., F. Muhale, S. Schloemann, S. M. Cohn, A. Morrison & W. F. Stenson: Basic fibroblast growth factor upregulates cyclooxygenase-2 in I407 cells through p38 MAP kinase. Am J Physiol Gastrointest Liver Physiol, 284, G269-79 (2003)
219. Singer, C. A., K. J. Baker, A. McCaffrey, D. P. AuCoin, M. A. Dechert & W. T. Gerthoffer: p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Am J Physiol Lung Cell Mol Physiol, 285, L1087-98 (2003)
220. Faour, W. H., A. Mancini, Q. W. He & J. A. Di Battista: T-cell-derived interleukin-17 regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of the p38 mitogen-activated protein kinase cascade: role of distal sequences in the 3'-untranslated region of COX-2 mRNA. Journal of Biological Chemistry, 278, 26897-907 (2003)
doi:10.1074/jbc.M212790200
221. Ridley, S. H., J. L. Dean, S. J. Sarsfield, M. Brook, A. R. Clark & J. Saklatvala: A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Letters, 439, 75-80 (1998)
doi:10.1016/S0014-5793(98)01342-8
222. Dean, J. L., M. Brook, A. R. Clark & J. Saklatvala: p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. Journal of Biological Chemistry, 274, 264-9 (1999)
doi:10.1074/jbc.274.1.264
223. Zhang, Z., H. Sheng, J. Shao, R. D. Beauchamp & R. N. DuBois: Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells. Neoplasia, 2, 523-30. (2000)
doi:10.1038/sj.neo.7900117
224. Lasa, M., M. Brook, J. Saklatvala & A. R. Clark: Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Molecular & Cellular Biology, 21, 771-80. (2001)
doi:10.1128/MCB.21.3.771-780.2001
225. Bachelor, M. A., A. L. Silvers & G. T. Bowden: The role of p38 in UVA-induced cyclooxygenase-2 expression in the human keratinocyte cell line, HaCaT. Oncogene, 21, 7092-9. (2002)
doi:10.1038/sj.onc.1205855
226. Tran, T., D. J. Fernandes, M. Schuliga, T. Harris, L. Landells & A. G. Stewart: Stimulus-dependent glucocorticoid-resistance of GM-CSF production in human cultured airway smooth muscle. Br J Pharmacol, 145, 123-31 (2005)
doi:10.1038/sj.bjp.0706174
227. McCormick, C. & D. Ganem: The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science, 307, 739-41 (2005)
doi:10.1126/science.1105779
228. Tebo, J., S. Der, M. Frevel, K. S. Khabar, B. R. Williams & T. A. Hamilton: Heterogeneity in Control of mRNA Stability by AU Rich Elements. Journal of Biological Chemistry, 28, 28 (2003)
229. Dai, Y., S. Datta, M. Novotny & T. A. Hamilton: TGF{beta} inhibits LPS-induced chemokine mRNA stabilization. Blood, 102, 1178-1185 (2003)
doi:10.1182/blood-2002-12-3771
230. Sirenko, O. I., A. K. Lofquist, C. T. DeMaria, J. S. Morris, G. Brewer & J. S. Haskill: Adhesion-dependent regulation of an A+U-rich element-binding activity associated with AUF1. Molecular And Cellular Biology, 17, 3898-906 (1997)
231. Parilla, N. W., V. S. Hughes, K. M. Lierl, H. R. Wong & K. Page: CpG DNA modulates interleukin 1beta-induced interleukin-8 expression in human bronchial epithelial (16HBE14o-) cells. Respir Res, 7, 84 (2006)
doi:10.1186/1465-9921-7-84
232. Henness, S., E. van Thoor, Q. Ge, C. L. Armour, J. M. Hughes & A. J. Ammit: IL-17A acts via p38 MAPK to increase stability of TNF-alpha-induced IL-8 mRNA in human ASM. Am J Physiol Lung Cell Mol Physiol, 290, L1283-90 (2006)
doi:10.1152/ajplung.00367.2005
233. Suswam, E. A., L. B. Nabors, Y. Huang, X. Yang & P. H. King: IL-1beta induces stabilization of IL-8 mRNA in malignant breast cancer cells via the 3' untranslated region: Involvement of divergent RNA-binding factors HuR, KSRP and TIAR. International Journal of Cancer, 113, 911-9 (2005)
doi:10.1002/ijc.20675
234. Ma, P., X. Cui, S. Wang, J. Zhang, E. V. Nishanian, W. Wang, R. A. Wesley & R. L. Danner: Nitric oxide post-transcriptionally up-regulates LPS-induced IL-8 expression through p38 MAPK activation. Journal of Leukocyte Biology, 76, 278-87 (2004)
doi:10.1189/jlb.1203653
235. Holtmann, H., J. Enninga, S. Kalble, A. Thiefes, A. Dorrie, M. Broemer, R. Winzen, A. Wilhelm, J. Ninomiya-Tsuji, K. Matsumoto, K. Resch & M. Kracht: The MAPKKK TAK1 plays a central role in coupling the IL-1 receptor to both, transcriptional and RNA-targetted mechanisms of gene regulation. Journal of Biological Chemistry (2000)
236. Jijon, H. B., W. J. Panenka, K. L. Madsen & H. G. Parsons: MAP kinases contribute to IL-8 secretion by intestinal epithelial cells via a posttranscriptional mechanism. Am J Physiol Cell Physiol, 283, C31-41. (2002)
237. Vockerodt, M., D. Pinkert, S. Smola-Hess, A. Michels, R. M. Ransohoff, H. Tesch & D. Kube: The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: importance of mRNA half-life regulation. International Journal of Cancer, 114, 598-605 (2005)
doi:10.1002/ijc.20759
238. Dhillon, N. K., F. Peng, R. M. Ransohoff & S. Buch: PDGF synergistically enhances IFN-gamma-induced expression of CXCL10 in blood-derived macrophages: implications for HIV dementia. Journal of Immunology, 179, 2722-30 (2007)
239. Sun, D. & A. Ding: MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat Immunol, 7, 375-81 (2006)
doi:10.1038/ni1308
240. Wong, H. R., K. E. Dunsmore, K. Page & T. P. Shanley: Heat shock-mediated regulation of MKP-1. Am J Physiol Cell Physiol (2005)
241. Mestas, J., S. P. Crampton, T. Hori & C. C. Hughes: Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA. International Immunology, 17, 737-47 (2005)
doi:10.1093/intimm/dxh255
242. Ming, X. F., G. Stoecklin, M. Lu, R. Looser & C. Moroni: Parallel and independent regulation of interleukin-3 mRNA turnover by phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase. Molecular & Cellular Biology, 21, 5778-89 (2001)
doi:10.1128/MCB.21.17.5778-5789.2001
243. Dodeller, F., A. Skapenko, J. R. Kalden, P. E. Lipsky & H. Schulze-Koops: The p38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells. European Journal of Immunology, 35, 3631-42 (2005)
doi:10.1002/eji.200535029
244. Zhao, W., M. Liu & K. L. Kirkwood: p38{alpha} Stabilizes Interleukin-6 mRNA via Multiple AU-rich Elements. Journal of Biological Chemistry, 283, 1778-85 (2008)
doi:10.1074/jbc.M707573200
245. Hershko, D. D., B. W. Robb, C. J. Wray, G. J. Luo & P. O. Hasselgren: Superinduction of IL-6 by cycloheximide is associated with mRNA stabilization and sustained activation of p38 map kinase and NF-kappaB in cultured caco-2 cells. J Cell Biochem, 91, 951-61 (2004)
doi:10.1002/jcb.20014
246. Miyazawa, K., A. Mori, H. Miyata, M. Akahane, Y. Ajisawa & H. Okudaira: Regulation of interleukin-1beta-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen-activated protein kinase. Journal of Biological Chemistry, 273, 24832-8 (1998)
doi:10.1074/jbc.273.38.24832
247. Wery-Zennaro, S., J. L. Zugaza, M. Letourneur, J. Bertoglio & J. Pierre: IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes. Oncogene, 19, 1596-604 (2000)
doi:10.1038/sj.onc.1203458
248. Norata, G. D., C. Banfi, A. Pirillo, E. Tremoli, A. Hamsten, A. L. Catapano & P. Eriksson: Oxidised-HDL3 induces the expression of PAI-1 in human endothelial cells. Role of p38MAPK activation and mRNA stabilization. Br J Haematol, 127, 97-104 (2004)
doi:10.1111/j.1365-2141.2004.05163.x
249. Ehlting, C., W. S. Lai, F. Schaper, E. D. Brenndorfer, R. J. Matthes, P. C. Heinrich, S. Ludwig, P. J. Blackshear, M. Gaestel, D. Haussinger & J. G. Bode: Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-alpha involves activation of the MKK6/p38MAPK/MK2 cascade. Journal of Immunology, 178, 2813-26 (2007)
250. Tew, S. R. & T. E. Hardingham: Regulation of SOX9 mRNA in human articular chondrocytes involving p38 MAPK activation and mRNA stabilization. Journal of Biological Chemistry, 281, 39471-9 (2006)
doi:10.1074/jbc.M604322200
251. Kishore, R., M. R. McMullen & L. E. Nagy: Stabilization of tumor necrosis factor alpha mRNA by chronic ethanol: role of A + U-rich elements and p38 mitogen-activated protein kinase signaling pathway. Journal of Biological Chemistry, 276, 41930-7 (2001)
doi:10.1074/jbc.M107181200
252. Montero, L. & Y. Nagamine: Regulation by p38 mitogen-activated protein kinase of adenylate- and uridylate-rich element-mediated urokinase-type plasminogen activator (uPA) messenger RNA stability and uPA-dependent in vitro cell invasion. Cancer Research, 59, 5286-93 (1999)
253. Pages, G., E. Berra, J. Milanini, A. P. Levy & J. Pouyssegur: Stress-activated protein kinases (JNK and p38/HOG) are essential for vascular endothelial growth factor mRNA stability. Journal of Biological Chemistry, 275, 26484-91. (2000)
doi:10.1074/jbc.M002104200
254. Westmark, C. J. & J. S. Malter: Extracellular-regulated kinase controls beta-amyloid precursor protein mRNA decay. Brain Res Mol Brain Res, 90, 193-201 (2001)
doi:10.1016/S0169-328X(01)00112-7
255. Headley, V. V., R. Tanveer, S. M. Greene, A. Zweifach & J. D. Port: Reciprocal regulation of beta-adrenergic receptor mRNA stability by mitogen activated protein kinase activation and inhibition. Molecular & Cellular Biochemistry, 258, 109-19 (2004)
doi:10.1023/B:MCBI.0000012841.03400.42
256. Tamura, M., S. Sebastian, S. Yang, B. Gurates, Z. Fang & S. E. Bulun: Interleukin-1beta elevates cyclooxygenase-2 protein level and enzyme activity via increasing its mRNA stability in human endometrial stromal cells: an effect mediated by extracellularly regulated kinases 1 and 2. Journal of Clinical Endocrinology & Metabolism, 87, 3263-73 (2002)
doi:10.1210/jc.87.7.3263
257. Xu, K., A. M. Robida & T. J. Murphy: Immediate-early MEK-1 dependent stabilization of rat smooth muscle cell cyclooxygenase-2 mRNA by Gaq-coupled receptor signaling. Journal of Biological Chemistry (2000)
258. Westmark, C. J. & J. S. Malter: Up-regulation of nucleolin mRNA and protein in peripheral blood mononuclear cells by extracellular-regulated kinase. Journal of Biological Chemistry, 276, 1119-26 (2001)
doi:10.1074/jbc.M009435200
259. Donadelli, M., E. Dalla Pozza, C. Costanzo, M. T. Scupoli, P. Piacentini, A. Scarpa & M. Palmieri: Increased stability of P21 (WAF1/CIP1) mRNA is required for ROS/ERK-dependent pancreatic adenocarcinoma cell growth inhibition by pyrrolidine dithiocarbamate. Biochimica et Biophysica Acta, 1763, 917-26 (2006)
doi:10.1016/j.bbamcr.2006.05.015
260. Yang, X., W. Wang, J. Fan, A. Lal, D. Yang, H. Cheng & M. Gorospe: Prostaglandin A2-mediated stabilization of p21 mRNA through an ERK-dependent pathway requiring the RNA-binding protein HuR. Journal of Biological Chemistry, 279, 49298-306 (2004)
doi:10.1074/jbc.M407535200
261. Sullivan, D. E., M. Ferris, D. Pociask & A. R. Brody: Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. Am J Respir Cell Mol Biol, 32, 342-9 (2005)
doi:10.1165/rcmb.2004-0288OC
262. Ming, X. F., M. Kaiser & C. Moroni: c-jun N-terminal kinase is involved in AUUUA-mediated interleukin-3 mRNA turnover in mast cells. EMBO Journal, 17, 6039-48 (1998)
doi:10.1093/emboj/17.20.6039
263. Lahti, A., U. Jalonen, H. Kankaanranta & E. Moilanen: c-Jun NH2-terminal kinase inhibitor anthra (1,9-cd)pyrazol-6 (2H)-one reduces inducible nitric-oxide synthase expression by destabilizing mRNA in activated macrophages. Molecular Pharmacology, 64, 308-15 (2003)
doi:10.1124/mol.64.2.308
264. Korhonen, R., K. Linker, A. Pautz, U. Forstermann, E. Moilanen & H. Kleinert: Post-transcriptional regulation of human inducible nitric-oxide synthase expression by the Jun N-terminal kinase. Molecular Pharmacology, 71, 1427-34 (2007)
doi:10.1124/mol.106.033449
Abbreviations: ARE, adenine/uridine-rich element; AREBP, ARE-binding protein; AUF, ARE/poly (U)-binding degradation factor; BRF, butyrate response factor; Chk, checkpoint kinase; COX-2, cyclooxygenase 2; CSF, colony stimulating factor; CXCL, chemokine CXC motif ligand; Dcp, decapping protein; ELAV, embryonic lethal abnormal vision; ERK, extracellular signal-regulated kinase; FBP, far upstream sequence element binding protein; FXR1P, fragile X-related protein 1; hnRNP, heterogeneous ribonucleoprotein; HuR, human antigen R; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase;JRE, JNK response element; KH, hnRNP K homology domain; KSRP, KH domain splicing regulatory protein; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MK, MAPK-activated kinase; MKK, MAPK kinase; Pin1, protein interacting with NIMA (never in mitosis A) 1; PMA, phorbol-12-myristate-13-acetate; RRM, RNA recognition motif; TIA-1, T cell-restricted intracellular antigen 1; TIAR, TIA-1-related protein; TNF, tumor necrosis factor; TTP, tristetraprolin; UTR, untranslated region; VEGF, vascular endothelial growth factor; YB-1, Y-box binding factor 1; ZFD, zinc finger domain; ZFP36, zinc finger protein of 36 kD; ZFP36L, ZFP36-like protein
Key Words: adenylate/uridylate-rich element, AUF, ERK, HuR, JNK, KSRP, mitogen-activated protein kinase, mRNA stability, mRNA translation, p38 MAPK, Post-transcriptional regulation, processing body, Protein Phosphorylation, Tristetraprolin, Cytokine Production, Inflammation, Review
Send correspondence to: Andrew R. Clark, Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK, Tel: 0208 383 4430, Fax: 0208 383 4496, E-mail:andy.clark@imperial.ac.uk