[Frontiers in Bioscience 14, 3925-3934, January 1, 2009]
Calcium fluxes deregulation in HTLV-I Infected T-cells and malignant transformation
Haidar Akl1, Bassam Badran1, Nabil El Zein2, Gratiela Dobirta1, Arsene Burny1 Philippe Martiat1
1
TABLE OF CONTENTS
1. ABSTRACT
The CD4+ T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-I) infection and termed; Adult T-cell Leukemia lymphoma (ATLL), is caused by defects in the mechanisms underlying cell proliferation and cell death. In the CD4+ T-cells, calcium ions are central for both phenomena. ATLL is associated with a marked hypercalcemia in many patients. The consequence of a defect in the Ca2+ signaling pathway for lymphocyte activation is characterized by an impaired NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defense. Fresh ATLL cells lack the TCR/CD3 and CD7 molecules on their surface. Whereas CD7 is a calcium transporter, reduction in calcium influx in response to T-cell activation was reported as a functional consequence of TCR/CD3 expression deficiency. Understanding these changes and identifying the molecular players involved might provide further insights on how to improve ATLL treatment.
2. INTRODUCTION
The Ca2+ ion is a second messenger responsible for regulating a diverse array of physiological processes (1). These processes range from muscle contraction to synaptic transmission, and from cellular proliferation to apoptosis (2). Ca2+ signals are generated by elevations in cytoplasmic Ca2+ that in turn activate downstream effectors including Ca2+-sensitive phosphatases, kinases, and proteases. In T-cells, the signaling cascade initiated by antigen binding to the TCR activates phospholipase Cg , generating IP3 which induces Ca2+ release from the endoplasmic reticulum (reviewed in (3-5)). The resulting elevation of cytoplasmic Ca2+ is shaped by complex processes involving not only release of Ca2+ from the ER, but also extracellular Ca2+ uptake through channels in the plasma membrane and uptake of Ca2+ by mitochondria. The result is a remarkable variety of cytoplasmic Ca2+ response patterns, including transient elevation of Ca2+, repetitive Ca2+ spikes (oscillations) or sustained Ca2+ elevation (6). Different patterns of Ca2+ elevation enable this single second messenger to encode a wide range of cellular processes. Large transient Ca2+ elevations preferentially activate NFkB and JNK, whereas NFAT is preferentially activated by sustained Ca2+ oscillations. In lymphocytes, information encoded by the frequency amplitude and shape of Ca2+ oscillations differentially regulates transcription factors (7,8). Since calcium-signaling regulates specific and fundamental cellular processes, it represents the ideal target of viral proteins, in order for the virus to control cellular functions and favor its persistence, multiplication and spread. A detailed analysis of reports focused on the impact of viral proteins on calcium-signaling has shown that virus-related elevations of cytosolic calcium levels allow increased viral protein expression (HIV-1, HSV-1/2), viral replication (HBx, enterovirus 2B, HTLV-1 p12I, HHV-8, EBV), viral maturation (rotavirus), viral release (enterovirus 2B) and cell immortalization (EBV). Interestingly, virus-induced decreased cytosolic calcium levels have been found to be associated with inhibition of immune cells functions (HIV-1 Tat, HHV-8 K15, EBV LMP2A). In human T-cell leukemia virus type 1 (HTLV-I) infections, viral proteins such as p12I and p13II are able to modulate intracellular calcium-signaling to control cell viability. Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from (HTLV-I)-infected mature CD4+ T-cells. Fresh ATLL cells lack TCR/CD3 and CD7 molecules on their surface. In this review we made an effort to understand how HTLV-I induces Ca2+ influx alterations and changes in immunophenotype, how this could be related or not to the leukemogenic process
3. THE HTLV-I ACCESSORY PROTEIN P12 (I) AND CALCIUM
Encoded by both singly spliced mRNA pX (ORF) 1 and doubly spliced mRNA pX-rex- (ORF) 1, p12 (I) plays a critical role in the establishment of HTLV-I infection and optimal infectivity in vivo (9) and of quiescent primary lymphocytes (10) HTLV-1 p12 (I) is a small hydrophobic protein, which contains four proline-rich SH3 domain binding motifs associated to regulation of signal transduction. The protein associates with the 16 kDa subunit of the vacuolar H+-ATPase, binds to IL-2 receptor β and γ chains and has been shown to enhance papillomavirus E5 transforming ability (reviewed by (11)). P12 (I) which is localized to the endoplasmic reticulum and to the Golgi, interacts with calreticulin and calnexin. It increases calcium release following protein kinase C activation by phorbol myristate acetate (PMA) leading to NFAT translocation into the nucleus (12). The nuclear translocation of NFAT boosts the T-cell proliferation and survival.
p12 (I) has been recently demonstrated to promote cell-to-cell viral spread by inducing LFA1 clustering on T-cells via a calcium-dependent mechanism (13). Several Ca2+ regulated proteins are affected by p12 (I)-dependent increase of (Ca2+)cyt, including the transcriptional co-activator, p300 (14, 15). Moreover, the HTLV-I regulatory protein P12 (I) activates NFAT nuclear translocation and NFAT directed transcription (16, 17). Overexpression of calreticulin was shown to block p12 (I)-dependent activation by preventing calcium-release from the ER and calcium entry through the plasma membrane (18). Interestingly, a new study showed that p12 (I) decreases NFAT (nuclear factor of activated T-cells) activation upon engagement of TCR/CD3 with anti-CD3 antibody by inhibiting LAT phosphorylation and, consequently, the phosphorylation of phospholipase C-gamma 1 and Vav (19). There is no contrast between the recent study and the previously reported positive effect of P12 (I) on NFAT activation following PMA stimulation, since, PMA stimulation bypasses TCR ligation. Thus, p12 (I) has contrasting effects on TCR signaling: it down-regulates TCR signaling in a LAT-dependent manner on the one hand, and on the other, it increases calcium release in a LAT-independent manner (20). Overall, p12 (I) is an essential HTLV-I factor for the establishment of a persistent viral infection. Moreover, p12 (I) downmodulates the expression of class I major histocompatibility complex (MHC) molecules (21). MHC suppression might help infected cells to escape the immune surveillance.
In addition to p12 (I), the HTLV-I accessory protein p13 (II) appeared to be implicated in Ca2+-signaling regulation. It was suggested that it acts through the formation of a channel, giving rise to a rapid flux of Ca2+ across the inner mitochondrial membrane (22).
4. TCR/CD3 SIGNAL TRANSDUCTION AFTER HTLV-I INFECTION
The specific recognition of antigen/MHC complexes by the TCR/CD3 complex leads to the phosphorylation - of an immunoreceptor tyrosine based activation motif (ITAM), present in the cytoplasmic domains of the CD3 subunits (23-28). At least four different signal transduction pathways are activated after the tyrosine phosphorylation of the ITAMs, including: the PLCg 1 pathway, the ras-mitogen activated protein kinase (MAPK) pathway, the phosphoinositol 3 kinase (PI3K) pathway, and the inducible T cell tyrosine kinase (Itk) pathway.
Activation of the PLCg 1 pathway leads to the generation of inositol 1,4,5 triphosphates (IP3) and diacylglycerol (DAG), which induce a calcium influx and activate PKC, respectively. This pathway converges on the activation of Ca2+-dependent calcineurin phosphatase activity, which in turn, when complexed with calmodulin and cyclophilin, acts on the cytoplasmic component of the NFAT (Nuclear factor of activated T-cells) family of transcription factors (29-31).
CD4+ T-cells from patients with ATLL are routinely characterized as having a CD3− or CD3low phenotype (32-34). Experimental infection of CD4+ T-cells with HTLV-I and HTLV-II (35,36) has also been associated with defects in TCR/CD3 expression and function. HTLV-I was found to ultimately downregulate CD3g , CD3d , CD3e , and CD3z gene transcripts leading to a TCR/CD3− surface phenotype after 200 days of in vitro infection. Recently, we have investigated the sequence of gene transcription; a decrease of CD3g followed by the subsequent progressive reduction in CD3d , then CD3e and CD3z mRNA has been observed (37). Alternatively, a reduction in calcium influx in response to T-cell activation was reported as a functional consequence of TCR/CD3 expression deficiency (38).
5. NFAT AND HTLV-I INDUCED CD4+ CELL TRANSFORMATION
The Nuclear factor of activated T-cells (NFAT) represents a family of transcription factors involved in the transcriptional regulation of cell surface receptors (TCR/CD3), cytokines (IL-2), as well as other transcription factors. NFAT proteins are translocated from the cytoplasm to the nucleus in response to Ca2+ mobilization and are returned to the cytoplasm when the Ca2+ signal is terminated (30, 39). NFAT proteins consist of at least five structurally related proteins, whose activity is regulated by a calcium-dependent phosphatase, calcineurin (40). After activation by calmodulin, calcineurin dephosphorylates the NFAT family members, allowing their translocation to the nucleus to activate genes controlled by NFAT (41-45). It has been shown that calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo (46). Previous studies have shown that Tax with TPA or ionomycin (47) or P12 (I) (48) activates the Il-2 expression through NFAT in Jurkat T-cell line. However, it should be noted that relatively few HTLV-I-infected T-cell lines express significant levels of IL-2 (49).
6. HTLV-I SILENCING AND CALCIUM
ATLL cells are characterized by a silenced HTLV-I provirus. Of note, the 5' LTR is frequently deleted or methylated, whereas the 3' LTR invariably remains intact in all cases of ATLL (50). However, It has been demonstrated that epigenetic mechanisms are responsible for HTLV-I-genes transcriptional silencing (51). DNA hypermethylation and histone modifications of the 5'-LTR appear to be important mechanisms by which HTLV-1 gene expression is repressed during viral latency (51, 52).
Eukaryotic DNA is packaged within the nucleus through its association with histone proteins, forming the fundamental repeating unit of chromatin, the nucleosome. Chromatin modifiers mobilize or eject nucleosomes and histone modifying complexes that add covalent modifications to histones (53). These post-translational modifications include, but are not limited to, acetylation, phosphorylation, methylation, ubiquitinylation and sumoylation (54). Some modifications, including acetylation and phosphorylation, are reversible and dynamic, and are often associated with inducible regulation of individual genes. In contrast, histone methylation appears to be more stable and seems to be involved in the cellular memory of the transcriptional status by fixing the chromatin organization in a heritable manner. It has been demonstrated that histone tails play a role in the folding process of the chromatin (55). Histone hyperacetylation is most commonly associated with active transcription (56). Acetylation of histones may augment transcription by neutralizing the positive charge on lysines, thus reducing histone association with negatively charged DNA. Addition of the acetyl groups to histones also decreases compaction between histones within nucleosomal arrays. Furthermore, acetylated lysines may provide a platform for the recruitment of other transcription factors that aid in gene expression (57).
The development of ChIP analysis allowed revealing the in vivo presence of Tax, a variety of ATF/CREB and AP-1 family members, and both p300 and CREB-binding protein (CBP) at the HTLV-I promoter (58). Moreover, Histones H3 and H4 were acetylated at specific sites at the level of the proviral genome and especially at the active viral promoter. Histone acetylation has been shown to play a pivotal role activating HTLV-I transcription in vitro. In addition, histone deacetylases (HDAC) are present at the promoter and inhibition of their activity using trichostatin A (TSA) was correlated with increased viral mRNA expression (59). Furthermore, a physical interaction between Tax and HDAC1 has been reported (60). Another HDAC inhibitor FR901228 induced apoptosis of Tax expressing and non-expressing HTLV-I infected T-cell lines and selective apoptosis of primary ATLL cells, especially those of patients with acute ATLL (61). However, the NF-κB inhibitor IkappaBalpha, constitutively phosphorylated in various HTLV-1-infected T-cell lines and ATLL-derived cell lines positively regulates cellular homeodomain-containing transcription factors through cytoplasmic sequestration of HDAC1 and HDAC3 (62). Indeed, histone H1 represses p300 acetyltransferase activity at the promoter of HTLV-I. Interestingly, Tax prevents that histone H1 negative effect without eliminating p300 from HTLV-I promoter (63). The coactivator-associated arginine methyltransferase 1 (CARM1), which methylates histone H3 and other proteins such as p300/CBP enhanced transcriptional activity of the HTLV-I LTR through direct interaction with Tax (64). A recent study has presented arginine methylation at histone H3R2 as a control mechanism of H3K4 trimethylation thus providing an insight into its function on chromatin (65).
Several studies have elucidated a correlation between Ca2+ signaling and chromatin remodeling. The results of Tarkka et al, suggested that nucleotide and Ca2+ binding might be important for H1-mediated chromatin changes (66). Protein kinase C (PKC)/ras and Ca2+-mediated membrane signaling has been shown to regulate hSWI/SNF chromatin remodeling during T-lymphocyte activation (67). The chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca2+-sensitive manner. Under basal conditions the transcription activity of SRF is negatively controlled by HDAC4 and this is reversed upon activation of Ca2+/CaMK signaling (68).
7. HTLV-I INFECTED CELLS: CD7, CALCIUM PATHWAYS AND APOPTOSIS
The CD7 antigen is a 40-kDa cell surface glycoprotein, belonging to the immunoglobulin (Ig) gene superfamily, and is one of the earliest antigens to appear on cells of the T-lymphocyte lineage. It is found on thymocytes and mature T-cells and is the most reliable clinical marker of T-cell acute lymphocytic leukemia. The CD7 gene is localized on chromosome 17 (69). The gene comprises 4 exons that span a 3.5 kb band and a promoter with no TATA boxes (70). Whereas, the function of CD7 is not yet fully understood, T-cells of patients with severe combined immunodeficiency do not express CD7 (71) and show defective T-cell proliferative responses to mitogens; however these T-cells were found to provide help for the differentiation of normal B cells into Ig-secreting cells. Abundant circulating B cells were detected. These findings supported the idea that the CD7 deficiency was related to a defect in T-cell precursors, and that CD7 plays an essential role not only in T-cell interactions but also in certain aspects of T-cell/B-cell interaction during early lymphoid development. It was reported that CD7 delivers a proapoptotic signal during galectin-1-induced T-cell death (72). Furthermore, CD4+ CD7- leukemic T-cells from patients with Sezary syndrome are protected from galectin-1-triggered T-cell death (73).
7.1. CD7 and ATLL
It has been shown that fresh ATLL cells are lacking CD7 at their surface (74). Later on, immunohistochemical studies in ATLL showed that the lack of CD7 expression was a typical characteristic of the malignant lymphocytes (75). It has also been shown that survival of acute myeloid leukemia cells requires phosphatidylinositol 3-kinase (PI3K) activation (76). Moreover, activation of PI3K/Akt signalling is involved in fibroblast Rat-1 transformation by HTLV-I (77). Interestingly, antibody ligation of CD7 leads to association with phospho-inositol 3-kinase and phosphatidylinositol 3,4,5-triphosphate formation in T lymphocytes (78). Furthermore, functional association of CD7 with PI3K has been reported (79). Our observations indicate that CD7 disappearance parallels PI3K activation and phosphorylation of Akt and Bad (80).
7.2. CD7 and calcium influx
It has been reported that mitogenic activation of T-cells increased CD7 cell surface expression (81). Ware et al showed later that induction of a transmembrane calcium flux generates signals that lead to CD7 gene transcription (82). Moreover, treatment with either a Ca2+ ionophore (A23187) or a cAMP analogue, dibutyryl cAMP (Bt,cAMP), stimulated CD7 expression on the surface of T lymphocytes, by increasing the steady-state-specific mRNA levels (83). Furthermore, ligation of CD7 with anti-CD7 mAb induces transmembrane Ca2+ flux in T and natural killer (NK) cells. The antithymocyte globulin (ATG)-Fresenius (ATG-F) enhanced acetylcholine (ACh) release, likely through transient increases in intracellular Ca2+ ( (Ca2+) (i)) mediated by CD7, which led to declines in intracellular ACh content (84).
7.3. Ca2+, apoptosis and cancer
Altered activity or expression of specific Ca2+ channels and pumps might be an adaptive response or might offer a survival advantage, such as resistance to apoptosis. A reduction in the Ca2+ content of the ER would be expected to reduce sensitivity to apoptosis (85). Moreover, the anti-apoptotic protein Bcl2, which is commonly deregulated in cancer (86) appears to modulate IP3-receptor Ca2+ channel activity on the ER Ca2+ stores (87-89) and reduces luminal ER Ca2+ levels through Ca2+ leakage when overexpressed in MCF-7 breast cancer cells (90). The reduction in ER Ca2+ means that Ca2+ release is insufficient to produce apoptosis through excessive mitochondrial Ca2+ accumulation (91, 92). Such changes in apoptosis sensitivity and proliferation are likely to bestow tumor-promoting properties by giving the cell a growth advantage. Recent studies also show that BCL2 inhibits pro-apoptotic Ca2+ signals, without inhibiting Ca2+ oscillation signals associated with cell survival (93). So it is possible to modify one set of Ca2+ responses (for example, apoptosis) without altering others. This highlights the potential for certain Ca2+ channels or pumps to be targeted in some cancers to induce apoptosis, concomitantly normal cells and normal physiological responses will not be severely compromised.
7.4. The PI3K/Akt/Bad pathway alteration after HTLV-I infection and calcium
We have recently shown an altered PI3K/Akt/Bad pathway after HTLV-I infection (80). Akt is a serine (Ser)/threonine (Thr) protein kinase which plays an important role in controlling cell growth and apoptosis (94). Through its PH domain, Akt binds to PIP3, activating Akt by phosphorylation. Activated Akt targets the apoptotic pathway, the cell cycle, and transcriptional translational machinery. The proapoptotic protein Bad is one of the main targets of the phosphorylated Akt. Given the critical role of the PI3K/Akt pathway in homeostasis and cell growth, it is not surprising that constitutive activation of the pathway contributes to the pathogenesis of many types of cancer (95). Similarly, the disruption of PI3K/Akt signalling has been effective against highly invasive breast cancer cells (96). However, the pro-apoptotic function of Bad is regulated by the Akt-mediated phosphorylation at Ser112 and Ser136 preventing its binding to its antiapoptotic partner Bcl-xL. Akt phosphorylates Bad both in vitro and in vivo and blocks the Bad induced death of primary neurons in a site-specific manner (97). Global gene expression studies in Mantle Cell Lymphoma (MCL) have shown an overexpression of elements of the PI3K/Akt pathway. Furthermore, a constitutive activation of Akt and Bad contributes to the pathogenesis of MCL (98).
Upstream of Akt there is the phosphatidylinositol 3-kinase (PI3K), which activates Akt in part via activation of 3′-phosphoinositide-dependent kinase-1 (99). The PI3K is composed of two subunits: A regulator one (p85) and a catalytic one p110 (100). Phosphoinositide 3-kinase (PI3K) and its downstream target Akt are activated in response to cytokine receptors (101). The resulting activation of PI3K/Akt pathway prevents many cells from undergoing apoptosis (102-104). Other studies have shown that survival of acute myeloid leukemia cells requires PI3K activation (105). Activation of PI3K/Akt signaling is involved in fibroblast Rat-1 transformation by HTLV-I (106). Taken all together, PI3K/Akt signaling pathway may be implicated in the cell transformation induced by HTLV-I. The Ca2+ influx alteration in HTLV-I-infected cells would thus reduce, credibly, the activity of the PLC. Indeed, PLC and PI3K compete for the same substrate, the phosphatidylinositol- (4,5) diphosphate (PIP2). The PLC transforms it into DAG and inositol (1,4,5) triphosphate (IP3). The PI3K transforms the PIP2 into phosphatidylinositol (3,4,5) triphosphate (PIP3). Given the Ca2+ influx perturbation observed in the HTLV-I-infected cells, we could imagine a deregulation of the balance between PLC and PI3K. On the other hand, it is well established that Ras activates PI3K. A mutation in Ras oncoprotein could be a second reason for the altered PI3K pathway after HTLV-I infection.
7.5. Galectins, CD7 and apoptosis
Galectins are a family of mammalian beta-galactoside- binding proteins that positively and negatively regulate T-cell death. Galectin-1 induces TCR apoptosis, but inhibits IL-2 production and cell proliferation (107). CD4CD7 leukemic T-cells from patients with Sezary syndrome (SS) are protected from galectin-1-triggered T-cell death. Expression of CD7 in CD7 HUT78 T-cells derived from a patient with SS rendered the cells susceptible to galectin-1-induced death (108). The deregulated expression of Galectin-3, which is expressed in various tissues and organs can result in tumor transformation and invasiveness, or confer propensity for tumor cell survival (109). Moreover, the majority of carcinomas express the galectin-3 protein (110). Increased expression of the LGALS3 gene was observed in human non-small cell lung cancer, and it was suggested to play a role in the process of metastasis in this malignancy but not in small cell lung cancer (111).
8. Conclusions and perspectives
At this stage of our review, and also based on our own experiments (37, 38), we are confronted with facts and hypotheses. Here are the facts. HTLV-I in vitro infection of an IL-2 dependent CD4-positive cell line (WE 17/10) results in a rapid (10 weeks) silencing of the proviral genome. However, a process has been launched, which continues over a longer period of time (1-2 years), despite this silencing, which ultimately leads to immunophenotypic (progressive loss of CD3 and CD7) and functional changes (acquisition of IL-2 independence, deregulation of intracellular Ca2+ influx, activation of the PI3K pathway and blockade of pro-apoptotic signaling). It is worth reminding that these phenomenons are fully present only at the stage of CD7-negative phenotype. We can speculate that the proviral silencing, probably through epigenetic mechanisms (51), has emerged along the evolution as a way to escape immune surveillance. Now, we must face hypotheses. Several established observations first: the absence of the TCR/CD3 complex has been shown to abrogate Ca2+ intracellular influx, through abrogation of the possibility to activate the PLCg 1 pathway, though maintaining Ca2+ oscillations necessary for cell survival (112). Changes of Ca2+ influx can induce chromatin remodeling, but cannot be responsible for proviral gene silencing, which occur much earlier. They could, however, activate other pathways. That this is the reason for the PI3K pathway to become constitutively activated is a pure speculation. On the other hand, Ca2+ influx abrogation is closely timely related with loss of CD7 expression (80) and there is a known relationship (113) between CD7 activation and increase in Ca2+ influx. Finally, the suppression of Ca2+ influx has been shown (114) to inhibit pro-apoptotic signals.
What can be held for sure is that HTLV-I infection initiates several processes that lead, after a long period of time, to a transformed phenotype: loss of dependence from growth factor (IL-2), resistance to apoptosis and growth advantage (80) ending up with a CD3-negative, CD7-negative monoclonal population. These processes go on despite early silencing of the proviral genes, which in turn, allows the cell to escape immune surveillance. In summary, all the conditions required to produce a T-cell malignancy are gathered.
The hypotheses, for which more work is needed, relate to two main topics: what is the way HTLV-I launches processes that persist and amplify after proviral silencing? Among the functional changes observed, which precedes which? Does one of the event cause another one, and in what order? Or are some of these changes occurring independently from some others? What would happen upon reactivation of Tax expression (by transfection) in these monoclonal T-cells? Understanding these changes, and their chronology, and identifying the molecular players involved may provide further insights into the process of transformation. This could allow finding ways to improve ATLL treatment, and target more specifically the malignant cells.
9. ACKNOWLEDGEMENTS
We thank the Belgian Fonds National de la Recherche Scientifique (FNRS, FRSM and Télévie), the Fonds Medic, the Friends of the Bordet Institute, and the Belgian Foundation against Cancer for their support and Pr E Sariban for his precious help. H Akl is a scientific collaborator of the FNRS-Télévie.
10. REFERENCES
1. Berridge M. J, P. Lipp and M. D. Bootman: The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1, 11-21 (2000)
doi:10.1038/35036035
2. Berridge M. J, M. D. Bootman and H. L. Roderick: Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4, 517-529 (2003)
doi:10.1038/nrm1155
3. Berridge M. J: The 1996 Massry Prize. Inositol trisphosphate and calcium: two interacting second messengers. Am J Nephrol 17, 1-11 (1997)
4. Lewis R. S.: Calcium oscillations in T-cells: mechanisms and consequences for gene expression. Biochem Soc Trans 31, 925-929 (2003)
5. Gallo E. M, K. Cante-Barrett and G. R. Crabtree: Lymphocyte calcium signaling from membrane to nucleus. Nat Immunol 7, 25-32 (2006)
doi:10.1038/ni1295
6. Randriamampita C and A. Trautmann: Ca2+ signals and T lymphocytes; "New mechanisms and functions in Ca2+ signalling". Biol Cell 96, 69-78 (2004)
doi:10.1016/j.biolcel.2003.10.008
7. Dolmetsch R. E, R. S. Lewis, C. C. Goodnow and J. I. Healy: Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855-858 (1997)
doi:10.1038/386855a0
8. Dolmetsch R. E, K. Xu and R. S. Lewis: Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933-936 (1998)
doi:10.1038/31960
9. Collins N. D, G. C. Newbound, B. Albrecht, J. L. Beard, L. Ratner and M. D. Lairmore: Selective ablation of human T-cell lymphotropic virus type 1 p12I reduces viral infectivity in vivo. Blood 91, 4701-4707 (1998)
10. Albrecht B, N. D. Collins, M. T. Burniston, J. W. Nisbet, L. Ratner, P. L. Green and M. D. Lairmore: Human T-lymphotropic virus type 1 open reading frame I p12 (I) is required for efficient viral infectivity in primary lymphocytes. J Virol 74, 9828-9835 (2000)
doi:10.1128/JVI.74.21.9828-9835.2000
11. Nicot C, R. L. Harrod, V. Ciminale and G. Franchini: Human T-cell leukemia/lymphoma virus type 1 nonstructural genes and their functions. Oncogene 24, 6026-6034 (2005)
doi:10.1038/sj.onc.1208977
12. Ding W, B. Albrecht, R. Luo, W. Zhang, J. R. Stanley, G. C. Newbound and M. D. Lairmore: Endoplasmic reticulum and cis-Golgi localization of human T-lymphotropic virus type 1 p12 (I): association with calreticulin and calnexin. J Virol 75, 7672-7682 (2001)
doi:10.1128/JVI.75.16.7672-7682.2001
13. Kim S. J, A. M. Nair, S. Fernandez, L. Mathes and M. D. Lairmore: Enhancement of LFA-1-mediated T cell adhesion by human T lymphotropic virus type 1 p12I1. J Immunol 176, 5463-5470 (2006)
14. Nair A. M, B. Michael, A. Datta, S. Fernandez and M. D. Lairmore: Calcium-dependent enhancement of transcription of p300 by human T-lymphotropic type 1 p12I. Virology 353, 247-257 (2006)
doi:10.1016/j.virol.2006.06.005
15. Nair A, B. Michael, H. Hiraragi, S. Fernandez, G. Feuer, K. Boris-Lawrie and M. Lairmore: Human T lymphotropic virus type 1 accessory protein p12I modulates calcium-mediated cellular gene expression and enhances p300 expression in T lymphocytes. AIDS Res Hum Retroviruses 21, 273-284 (2005)
doi:10.1089/aid.2005.21.273
16. Albrecht B, C. D. D'Souza, W. Ding, S. Tridandapani, K. M. Coggeshall and M. D. Lairmore: Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12 (I) J Virol 76, 3493-3501 (2002)
doi:10.1128/JVI.76.7.3493-3501.2002
17. Kim S. J, W. Ding, B. Albrecht, P. L. Green and M. D. Lairmore: A conserved calcineurin-binding motif in human T lymphotropic virus type 1 p12I functions to modulate nuclear factor of activated T cell activation. J Biol Chem 278, 15550-15557 (2003)
doi:10.1074/jbc.M210210200
18. Ding W, B. Albrecht, R. E. Kelley, N. Muthusamy, S. J. Kim, R. A. Altschuld and M. D. Lairmore: Human T-cell lymphotropic virus type 1 p12 (I) expression increases cytoplasmic calcium to enhance the activation of nuclear factor of activated T cells. J Virol 76, 10374-10382 (2002)
doi:10.1128/JVI.76.20.10374-10382.2002
19. Fukumoto R, M. Dundr, C. Nicot, A. Adams, V. W. Valeri, L. E. Samelson and G. Franchini: Inhibition of T-cell receptor signal transduction and viral expression by the linker for activation of T cells-interacting p12 (I) protein of human T-cell leukemia/lymphoma virus type 1. J Virol 81, 9088-9099 (2007)
doi:10.1128/JVI.02703-06
20. Fukumoto R, M. Dundr, C. Nicot, A. Adams, V. W. Valeri, L. E. Samelson and G. Franchini: Inhibition of T-cell receptor signal transduction and viral expression by the linker for activation of T cells-interacting p12 (I) protein of human T-cell leukemia/lymphoma virus type 1. J Virol 81, 9088-9099 (2007)
doi:10.1128/JVI.02703-06
21. Johnson J. M, C. Nicot, J. Fullen, V. Ciminale, L. Casareto, J. C. Mulloy, S. Jacobson and G. Franchini: Free major histocompatibility complex class I heavy chain is preferentially targeted for degradation by human T-cell leukemia/lymphotropic virus type 1 p12 (I) protein. J Virol 75, 6086-6094 (2001)
doi:10.1128/JVI.75.13.6086-6094.2001
22. D'Agostino D. M, M. Silic-Benussi, H. Hiraragi, M. D. Lairmore and V. Ciminale: The human T-cell leukemia virus type 1 p13II protein: effects on mitochondrial function and cell growth. Cell Death Differ 12 Suppl 1, 905-915 (2005)
doi:10.1038/sj.cdd.4401576
23. Weiss A and D. R. Littman: Signal transduction by lymphocyte antigen receptors. Cell 76, 263-274 (1994)
doi:10.1016/0092-8674(94)90334-4
24. Baniyash M, P. Garcia-Morales, J. S. Bonifacino, L. E. Samelson and R. D. Klausner: Disulfide linkage of the zeta and eta chains of the T cell receptor. Possible identification of two structural classes of receptors. J Biol Chem 263, 9874-9878 (1988)
25. Alarcon B, B. Berkhout, J. Breitmeyer and C. Terhorst: Assembly of the human T cell receptor-CD3 complex takes place in the endoplasmic reticulum and involves intermediary complexes between the CD3-gamma.delta.epsilon core and single T cell receptor alpha or beta chains. J Biol Chem 263, 2953-2961 (1988)
26. Berkhout B, B. Alarcon and C. Terhorst: Transfection of genes encoding the T cell receptor-associated CD3 complex into COS cells results in assembly of the macromolecular structure. J Biol Chem 263, 8528-8536 (1988)
27. Iwashima M, B. A. Irving, N. S. van Oers, A. C. Chan and A. Weiss: Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136-1139 (1994)
doi:10.1126/science.7509083
28. Neudorf S. M, M. M. Jones, B. M. McCarthy, J. A. Harmony and E. M. Choi: The CD4 molecule transmits biochemical information important in the regulation of T lymphocyte activity. Cell Immunol 125, 301-314 (1990)
doi:10.1016/0008-8749(90)90086-7
29. Clipstone N. A and G. R. Crabtree: Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695-697 (1992)
doi:10.1038/357695a0
30. Crabtree G. R and N. A. Clipstone: Signal transmission between the plasma membrane and nucleus of T lymphocytes. Annu Rev Biochem 63, 1045-1083 (1994)
doi:10.1146/annurev.bi.63.070194.005145
31. Northrop J. P, S. N. Ho, L. Chen, D. J. Thomas, L. A. Timmerman, G. P. Nolan, A. Admon and G. R. Crabtree: NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369, 497-502 (1994)
doi:10.1038/369497a0
32. Yokote T, T. Akioka, S. Oka, S. Hara, K. Kobayashi, H. Nakajima, T. Yamano, T. Ikemoto, A. Shimizu, M. Tsuji and T. Hanafusa: Flow cytometric immunophenotyping of adult T-cell leukemia/lymphoma using CD3 gating. Am J Clin Pathol 124, 199-204 (2005)
doi:10.1309/KEN4-MXM5-Y9A1-GEMP
33. Tsuda H and K. Takatsuki: Specific decrease in T3 antigen density in adult T-cell leukaemia cells: I. Flow microfluorometric analysis. Br J Cancer 50, 843-845 (1984)
34. Matsuoka M, T. Hattori, T. Chosa, H. Tsuda, S. Kuwata, M. Yoshida, T. Uchiyama and K. Takatsuki: T3 surface molecules on adult T cell leukemia cells are modulated in vivo. Blood 67, 1070-1076 (1986)
35. Yssel H, M. R. de Waal, D. Duc, D. Blanchard, L. Gazzolo, J. E. de Vries and H. Spits: Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells. J Immunol 142, 2279-2289 (1989)
36. de Waal M, H. Yssel, H. Spits, J. E. de Vries, J. Sancho, C. Terhorst and B. Alarcon: Human T cell leukemia virus type I prevents cell surface expression of the T cell receptor through down-regulation of the CD3-gamma, -delta, -epsilon, and -zeta genes. J Immunol 145, 2297-2303 (1990)
37. Akl H, B. Badran, G. Dobirta, G. Manfouo-Foutsop, M. Moschitta, M. Merimi, A. Burny, P. Martiat and K. E. Willard-Gallo: Progressive loss of CD3 expression after HTLV-I infection results from chromatin remodeling affecting all the CD3 genes and persists despite early viral genes silencing. Virol J 4, 85 (2007)
doi:10.1186/1743-422X-4-85
38. Le Deist F, G. Thoenes, J. Corado, B. Lisowska-Grospierre and A. Fischer: Immunodeficiency with low expression of the T cell receptor/CD3 complex. Effect on T lymphocyte activation. Eur J Immunol 21, 1641-1647 (1991)
doi:10.1002/eji.1830210709
39. Rao A, C. Luo and P. G. Hogan: Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15, 707-747 (1997)
doi:10.1146/annurev.immunol.15.1.707
40. Shibasaki F, E. R. Price, D. Milan and F. McKeon: Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature 382, 370-373 (1996)
doi:10.1038/382370a0
41. Northrop J. P, S. N. Ho, L. Chen, D. J. Thomas, L. A. Timmerman, G. P. Nolan, A. Admon and G. R. Crabtree: NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369, 497-502 (1994)
doi:10.1038/369497a0
42. Flanagan W. M, B. Corthesy, R. J. Bram and G. R. Crabtree: Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352, 803-807 (1991)
doi:10.1038/352803a0
43. Shaw K. T, A. M. Ho, A. Raghavan, J. Kim, J. Jain, J. Park, S. Sharma, A. Rao and P. G. Hogan: Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci U S A 92, 11205-11209 (1995)
doi:10.1073/pnas.92.24.11205
44. Loh C, J. A. Carew, J. Kim, P. G. Hogan and A. Rao: T-cell receptor stimulation elicits an early phase of activation and a later phase of deactivation of the transcription factor NFAT1. Mol Cell Biol 16, 3945-3954 (1996)
45. Loh C, K. T. Shaw, J. Carew, J. P. Viola, C. Luo, B. A. Perrino and A. Rao: Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity. J Biol Chem 271, 10884-10891 (1996)
doi:10.1074/jbc.271.18.10884
46. Medyouf H, H. Alcalde, C. Berthier, M. C. Guillemin, N. R. dos Santos, A. Janin, D. Decaudin, T. H. de and J. Ghysdael: Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 13, 736-741 (2007)
doi:10.1038/nm1588
47. Good L, S. B. Maggirwar and S. C. Sun: Activation of the IL-2 gene promoter by HTLV-I tax involves induction of NF-AT complexes bound to the CD28-responsive element. EMBO J 15, 3744-3750 (1996)
48. Albrecht B, C. D. D'Souza, W. Ding, S. Tridandapani, K. M. Coggeshall and M. D. Lairmore: Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12 (I) J Virol 76, 3493-3501 (2002)
doi:10.1128/JVI.76.7.3493-3501.2002
49. Arya S. K, R. C. Gallo, B. H. Hahn, G. M. Shaw, M. Popovic, S. Z. Salahuddin and F. Wong-Staal: Homology of genome of AIDS-associated virus with genomes of human T- cell leukemia viruses. Science 225, 927-930 (1984)
doi:10.1126/science.6089333
50. Satou Y, J. Yasunaga, M. Yoshida and M. Matsuoka: HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc Natl Acad Sci U S A 103, 720-725 (2006)
doi:10.1073/pnas.0507631103
51. Taniguchi Y, K. Nosaka, J. Yasunaga, M. Maeda, N. Mueller, A. Okayama and M. Matsuoka: Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms. Retrovirology 2, 64 (2005)
doi:10.1186/1742-4690-2-64
52. Koiwa T, A. Hamano-Usami, T. Ishida, A. Okayama, K. Yamaguchi, S. Kamihira and T. Watanabe: 5'-long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo. J Virol 76, 9389-9397 (2002)
doi:10.1128/JVI.76.18.9389-9397.2002
53. Narlikar G. J, H. Y. Fan and R. E. Kingston: Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475-487 (2002)
doi:10.1016/S0092-8674(02)00654-2
54. Lachner M, R. J. O'Sullivan and T. Jenuwein: An epigenetic road map for histone lysine methylation. J Cell Sci 116, 2117-2124 (2003)
doi:10.1242/jcs.00493
55. Carruthers L. M and J. C. Hansen: The core histone N termini function independently of linker histones during chromatin condensation. J Biol Chem 275, 37285-37290 (2000)
doi:10.1074/jbc.M006801200
56. Eberharter A and P. B. Becker: Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep 3, 224-229 (2002)
doi:10.1093/embo-reports/kvf053
57. Narlikar G. J, H. Y. Fan and R. E. Kingston: Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475-487 (2002)
doi:10.1016/S0092-8674(02)00654-2
58. Lemasson I, N. J. Polakowski, P. J. Laybourn and J. K. Nyborg: Transcription factor binding and histone modifications on the integrated proviral promoter in human T-cell leukemia virus-I-infected T-cells. J Biol Chem 277, 49459-49465 (2002)
doi:10.1074/jbc.M209566200
59. Lu H, C. A. Pise-Masison, R. Linton, H. U. Park, R. L. Schiltz, V. Sartorelli and J. N. Brady: Tax relieves transcriptional repression by promoting histone deacetylase 1 release from the human T-cell leukemia virus type 1 long terminal repeat. J Virol 78, 6735-6743 (2004)
doi:10.1128/JVI.78.13.6735-6743.2004
60. Ego T, Y. Ariumi and K. Shimotohno: The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression. Oncogene 21, 7241-7246 (2002)
doi:10.1038/sj.onc.1205701
61. Mori N, T. Matsuda, M. Tadano, T. Kinjo, Y. Yamada, K. Tsukasaki, S. Ikeda, Y. Yamasaki, Y. Tanaka, T. Ohta, T. Iwamasa, M. Tomonaga and N. Yamamoto: Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells. J Virol 78, 4582-4590 (2004)
doi:10.1128/JVI.78.9.4582-4590.2004
62. Viatour P, S. Legrand-Poels, L. C. van, M. Warnier, M. P. Merville, J. Gielen, J. Piette, V. Bours and A. Chariot: Cytoplasmic IkappaBalpha increases NF-kappaB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3. J Biol Chem 278, 46541-46548 (2003)
63. Konesky K. L, J. K. Nyborg and P. J. Laybourn: Tax abolishes histone H1 repression of p300 acetyltransferase activity at the human T-cell leukemia virus type 1 promoter. J Virol 80, 10542-10553 (2006)
doi:10.1128/JVI.00631-06
64. Jeong S. J, H. Lu, W. K. Cho, H. U. Park, C. Pise-Masison and J. N. Brady: Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell lymphotropic virus type 1 long terminal repeat through direct interaction with Tax. J Virol 80, 10036-10044 (2006)
doi:10.1128/JVI.00186-06
65. Kirmizis A, H. Santos-Rosa, C. J. Penkett, M. A. Singer, M. Vermeulen, M. Mann, J. Bahler, R. D. Green and T. Kouzarides: Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature 449, 928-932 (2007)
doi:10.1038/nature06160
66. Tarkka T, J. Oikarinen and T. Grundstrom: Nucleotide and calcium-induced conformational changes in histone H1. FEBS Lett 406, 56-60 (1997)
doi:10.1016/S0014-5793(97)00238-X
67. Zhao K, W. Wang, O. J. Rando, Y. Xue, K. Swiderek, A. Kuo and G. R. Crabtree: Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625-636 (1998)
doi:10.1016/S0092-8674(00)81633-5
68. Davis F. J, M. Gupta, B. Camoretti-Mercado, R. J. Schwartz and M. P. Gupta: Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4. Implications in cardiac muscle gene regulation during hypertrophy. J Biol Chem 278, 20047-20058 (2003)
doi:10.1074/jbc.M209998200
69. Baker E, M. S. Sandrin, O. M. Garson, G. R. Sutherland, I. F. McKenzie and L. M. Webber: Localization of the cell surface antigen CD7 by chromosomal in situ hybridization. Immunogenetics 31, 412-413 (1990)
doi:10.1007/BF02115022
70. Schanberg L. E, D. E. Fleenor, J. Kurtzberg, B. F. Haynes and R. E. Kaufman: Isolation and characterization of the genomic human CD7 gene: structural similarity with the murine Thy-1 gene. Proc Natl Acad Sci U S A 88, 603-607 (1991)
doi:10.1073/pnas.88.2.603
71. Jung L. K, S. M. Fu, T. Hara, N. Kapoor and R. A. Good: Defective expression of T cell-associated glycoprotein in severe combined immunodeficiency. J Clin Invest 77, 940-946 (1986)
doi:10.1172/JCI112393
72. Pace K. E, H. P. Hahn, M. Pang, J. T. Nguyen and L. G. Baum: CD7 delivers a pro-apoptotic signal during galectin-1-induced T cell death. J Immunol 165, 2331-2334 (2000)
73. Rappl G, H. Abken, J. M. Muche, W. Sterry, W. Tilgen, S. Andre, H. Kaltner, S. Ugurel, H. J. Gabius and U. Reinhold: CD4+CD7- leukemic T cells from patients with Sezary syndrome are protected from galectin-1-triggered T cell death. Leukemia 16, 840-845 (2002)
doi:10.1038/sj.leu.2402438
74. Morimoto C, T. Matsuyama, C. Oshige, H. Tanaka, T. Hercend, E. L. Reinherz and S. F. Schlossman: Functional and phenotypic studies of Japanese adult T cell leukemia cells. J Clin Invest 75, 836-843 (1985)
doi:10.1172/JCI111780
75. Dahmoush L, Y. Hijazi, E. Barnes, M. Stetler-Stevenson and A. Abati: Adult T-cell leukemia/lymphoma: a cytopathologic, immunocytochemical, and flow cytometric study. Cancer 96, 110-116 (2002)
76. Xu Q, S. E. Simpson, T. J. Scialla, A. Bagg and M. Carroll: Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102, 972-980 (2003)
doi:10.1182/blood-2002-11-3429
77. Liu Y, Y. Wang, M. Yamakuchi, S. Masuda, T. Tokioka, S. Yamaoka, I. Maruyama and I. Kitajima: Phosphoinositide-3 kinase-PKB/Akt pathway activation is involved in fibroblast Rat-1 transformation by human T-cell leukemia virus type I tax. Oncogene 20, 2514-2526 (2001)
doi:10.1038/sj.onc.1204364
78. Ward S. G, R. Parry, C. LeFeuvre, D. M. Sansom, J. Westwick and A. I. Lazarovits: Antibody ligation of CD7 leads to association with phosphoinositide 3-kinase and phosphatidylinositol 3,4,5-trisphosphate formation in T lymphocytes. Eur J Immunol 25, 502-507 (1995)
doi:10.1002/eji.1830250229
79. Lee D. M, D. D. Patel, A. M. Pendergast and B. F. Haynes: Functional association of CD7 with phosphatidylinositol 3-kinase: interaction via a YEDM motif. Int Immunol 8, 1195-1203 (1996)
doi:10.1093/intimm/8.8.1195
80. Akl H, B. M. Badran, N. E. Zein, F. Bex, C. Sotiriou, K. E. Willard-Gallo, A. Burny and P. Martiat: HTLV-I infection of WE17/10 CD4+ cell line leads to progressive alteration of Ca2+ influx that eventually results in loss of CD7 expression and activation of an antiapoptotic pathway involving AKT and BAD which paves the way for malignant transformation. Leukemia 21, 788-796 (2007)
81. Morishima Y, M. Kobayashi, S. Y. Yang, N. H. Collins, M. K. Hoffmann and B. Dupont: Functionally different T lymphocyte subpopulations determined by their sensitivity to complement-dependent cell lysis with the monoclonal antibody 4A. J Immunol 129, 1091-1098 (1982)
82. Ware R. E, M. K. Hart and B. F. Haynes: Induction of T cell CD7 gene transcription by nonmitogenic ionomycin-induced transmembrane calcium flux. J Immunol 147, 2787-2794 (1991)
83. Rincon M, A. Tugores and M. Lopez-Botet: Cyclic AMP and calcium regulate at a transcriptional level the expression of the CD7 leukocyte differentiation antigen. J Biol Chem 267, 18026-18031 (1992)
84. Fujii T, N. Ushiyama, K. Hosonuma, A. Suenaga and K. Kawashima: Effects of human antithymocyte globulin on acetylcholine synthesis, its release and choline acetyltransferase transcription in a human leukemic T-cell line. J Neuroimmunol 128, 1-8 (2002)
doi:10.1016/S0165-5728(02)00111-X
85. Pinton P and R. Rizzuto: Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ 13, 1409-1418 (2006)
doi:10.1038/sj.cdd.4401960
86. Cory S, D. C. Huang and J. M. Adams: The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22, 8590-8607 (2003)
doi:10.1038/sj.onc.1207102
87. Pinton P and R. Rizzuto: Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ 13, 1409-1418 (2006)
doi:10.1038/sj.cdd.4401960
88. Zhong F, M. C. Davis, K. S. McColl and C. W. Distelhorst: Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation. J Cell Biol 172, 127-137 (2006)
doi:10.1083/jcb.200506189
89. Chen R., I. Valencia, F. Zhong, K. S. McColl, H. L. Roderick, M. D. Bootman, M. J. Berridge, S. J. Conway, A. B. Holmes, G. A. Mignery, P. Velez and C. W. Distelhorst: Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J Cell Biol 166, 193-203 (2004)
doi:10.1083/jcb.200309146
90. Brini M, D. Bano, S. Manni, R. Rizzuto and E. Carafoli: Effects of PMCA and SERCA pump overexpression on the kinetics of cell Ca (2+) signalling. EMBO J 19, 4926-4935 (2000)
doi:10.1093/emboj/19.18.4926
91. Rizzuto R, P. Pinton, D. Ferrari, M. Chami, G. Szabadkai, P. J. Magalhaes, V. F. Di and T. Pozzan: Calcium and apoptosis: facts and hypotheses. Oncogene 22, 8619-8627 (2003)
doi:10.1038/sj.onc.1207105
92. Pinton P and R. Rizzuto: Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ 13, 1409-1418 (2006)
doi:10.1038/sj.cdd.4401960
93. Zhong F, M. C. Davis, K. S. McColl and C. W. Distelhorst: Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation. J Cell Biol 172, 127-137 (2006)
doi:10.1083/jcb.200506189
94. Franke T. F, D. R. Kaplan and L. C. Cantley: PI3K: downstream AKTion blocks apoptosis. Cell 88, 435-437 (1997)
doi:10.1016/S0092-8674(00)81883-8
95. Luo J, B. D. Manning and L. C. Cantley: Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4, 257-262 (2003)
doi:10.1016/S1535-6108(03)00248-4
96. Albert J. M, K. W. Kim, C. Cao and B. Lu: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther 5, 1183-1189 (2006)
doi:10.1158/1535-7163.MCT-05-0400
97. del P. L, M. Gonzalez-Garcia, C. Page, R. Herrera and G. Nunez: Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687-689 (1997)
doi:10.1126/science.278.5338.687
98. Rudelius M, S. Pittaluga, S. Nishizuka, T. H. Pham, F. Fend, E. S. Jaffe, L. Quintanilla-Martinez and M. Raffeld: Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 108, 1668-1676 (2006)
doi:10.1182/blood-2006-04-015586
99. Franke T. F, D. R. Kaplan and L. C. Cantley: PI3K: downstream AKTion blocks apoptosis. Cell 88, 435-437 (1997)
doi:10.1016/S0092-8674(00)81883-8
100. Hiles I. D, M. Otsu, S. Volinia, M. J. Fry, I. Gout, R. Dhand, G. Panayotou, F. Ruiz-Larrea, A. Thompson, N. F. Totty et al: Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70, 419-429 (1992)
doi:10.1016/0092-8674(92)90166-A
101. Kelly-Welch A. E, E. M. Hanson, M. R. Boothby and A. D. Keegan: Interleukin-4 and interleukin-13 signaling connections maps. Science 300, 1527-1528 (2003)
doi:10.1126/science.1085458
102. Duronio V, M. P. Scheid and S. Ettinger: Downstream signalling events regulated by phosphatidylinositol 3-kinase activity. Cell Signal 10, 233-239 (1998)
doi:10.1016/S0898-6568(97)00129-0
103. Franke T. F, D. R. Kaplan and L. C. Cantley: PI3K: downstream AKTion blocks apoptosis. Cell 88, 435-437 (1997)
doi:10.1016/S0092-8674(00)81883-8
104. Hemmings B. A: Akt signaling: linking membrane events to life and death decisions. Science 275, 628-630 (1997)
doi:10.1126/science.275.5300.628
105. Xu Q, S. E. Simpson, T. J. Scialla, A. Bagg and M. Carroll: Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102, 972-980 (2003)
doi:10.1182/blood-2002-11-3429
106. Liu Y, Y. Wang, M. Yamakuchi, S. Masuda, T. Tokioka, S. Yamaoka, I. Maruyama and I. Kitajima: Phosphoinositide-3 kinase-PKB/Akt pathway activation is involved in fibroblast Rat-1 transformation by human T-cell leukemia virus type I tax. Oncogene 20, 2514-2526 (2001)
doi:10.1038/sj.onc.1204364
107. Vespa G. N, L. A. Lewis, K. R. Kozak, M. Moran, J. T. Nguyen, L. G. Baum and M. C. Miceli: Galectin-1 specifically modulates TCR signals to enhance TCR apoptosis but inhibit IL-2 production and proliferation. J Immunol 162, 799-806 (1999)
108. Pace K. E, H. P. Hahn, M. Pang, J. T. Nguyen and L. G. Baum: CD7 delivers a pro-apoptotic signal during galectin-1-induced T cell death. J Immunol 165, 2331-2334 (2000)
109. Hsu D. K, C. A. Dowling, K. C. Jeng, J. T. Chen, R. Y. Yang and F. T. Liu: Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma. Int J Cancer 81, 519-526 (1999)
doi:10.1002/(SICI)1097-0215(19990517)81:4<519::AID-IJC3>3.0.CO;2-0
110. Martins L, S. E. Matsuo, K. N. Ebina, M. A. Kulcsar, C. U. Friguglietti and E. T. Kimura: Galectin-3 messenger ribonucleic acid and protein are expressed in benign thyroid tumors. J Clin Endocrinol Metab 87, 4806-4810 (2002)
doi:10.1210/jc.2002-020094
111. Yoshimura A, A. Gemma, Y. Hosoya, E. Komaki, Y. Hosomi, T. Okano, K. Takenaka, K. Matuda, M. Seike, K. Uematsu, S. Hibino, M. Shibuya, T. Yamada, S. Hirohashi and S. Kudoh: Increased expression of the LGALS3 (galectin 3) gene in human non-small-cell lung cancer. Genes Chromosomes Cancer 37, 159-164 (2003)
doi:10.1002/gcc.10205
112. Randriamampita C and A. Trautmann: Ca2+ signals and T lymphocytes; "New mechanisms and functions in Ca2+ signalling". Biol Cell 96, 69-78 (2004)
doi:10.1016/j.biolcel.2003.10.008
113. Fujii T, N. Ushiyama, K. Hosonuma, A. Suenaga and K. Kawashima: Effects of human antithymocyte globulin on acetylcholine synthesis, its release and choline acetyltransferase transcription in a human leukemic T-cell line. J Neuroimmunol 128, 1-8 (2002)
doi:10.1016/S0165-5728(02)00111-X
114. Rizzuto R, P. Pinton, D. Ferrari, M. Chami, G. Szabadkai, P. J. Magalhaes, V. F. Di and T. Pozzan: Calcium and apoptosis: facts and hypotheses. Oncogene 22, 8619-8627 (2003)
doi:10.1038/sj.onc.1207105
Key Words: HTLV-I, Ca2+, TCR/CD3,CD7, PI3K, Akt; Bad, Review
Send correspondence to: Haidar Akl, Experimental Hematology, Universite Libre de Bruxelles, Institut Jules Bordet 127 Boulvard de Waterloo, 1000 Bruxelles, Belgium, Tel: 32-0-2 5413730, Fax: 32-0-2 5423453, E- mail: haidar.akl@ulb.ac.be