[Frontiers in Bioscience E4, 331-341, January 1, 2012]
STIM and Orai in cellular proliferation and division
Raphael Courjaret1, Khaled Machaca1
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TABLE OF CONTENTS
1. ABSTRACT
Cellular proliferation and division are central processes in the development, survival and evolution of living systems. Transitioning into the cell division phase of the cell cycle encompasses dramatic remodeling of cellular organelles and signaling modules including Ca2+ signaling. As well, Ca2+ signals play important roles during progression through various stages of the cell cycle. A ubiquitous Ca2+ influx pathway that is activated based on intracellular Ca2+ store content is store-operated Ca2+ entry (soce). SOCE is activated through a complex interplay between a Ca2+ channel at the cell membrane, Orai1, and a Ca2+ sensor that localizes to the endoplasmic reticulum, STIM1. Herein, we discuss potential roles and regulation of STIM and Orai proteins during cellular proliferation.
2. CA2+ SIGNALING AND CELLULAR PROLIFERATION
Cellular proliferation depends on progression through the growth and division phases of the cell cycle. Typically, the cell cycle is divided into four phases starting with the first growth phase (G1) during which cells grow and accumulate components required for the ensuing DNA duplication phase (S-phase). Terminally differentiated cells exit the G1-phase to arrest in a so called G0 phase. Following the DNA duplication phase, cells go through a second growth phase, G2, before entering the short but dramatic division phase, M-phase. This results in the production of two daughter cells with an equivalent cellular organelle and DNA complement allowing the continuation of cellular growth and division in the next generation (1). For the cell cycle to successfully support cellular proliferation it has to be sequential G1-S-G2-M, that is cells cannot undergo cellular division before having duplicated their DNA as this will result in cellular demise. In addition the cycle is unidirectional to prevent DNA endoreplication for example and ensure cellular survival. To guarantee the sequential and unidirectional nature of the cell cycle critical checkpoints and feedback loops are incorporated in the signaling cascades regulating cell cycle progression. Early embryonic cell cycles in the frog for example deviate from the typical cycle as they lack the growth phases and encompassed only the DNA synthesis and division phase. This is due to the need for rapid cell division at this stage of development, and the fact that macromolecular components required for cell cycle progression are stored in the large egg before fertilization.
Ca2+ signals have been implicated at several stages during cell cycle progression (2). Ca2+ is a fitting second messenger in that context given the versatility and specificity it affords based on its spatial, temporal and amplitudes dynamics (3; 4). Ca2+ signals have been shown to be important for nuclear envelope breakdown during prophase, DNA condensation, anaphase onset, and cytokinesis (5-12). Notably some interesting differences were documented in terms of the role of Ca2+ signals between the mitotic and meiotic cell cycles, including the requirement for Ca2+ signals during the breakdown of the nuclear envelope. In contrast to mitosis, Ca2+ signals are dispensable for nuclear envelope breakdown during meiosis (13; 14).
These dependencies on Ca2+ signals at various stages of the cell cycle have been translated to downstream Ca2+ signaling modules including calmodulin (CaM), Ca2+-CaM dependent protein kinase II (CaMKII) and calcineurin among others. Progression through the cell cycle is associated with alterations in the levels of CaM expression with an increase during the G1-S transition (15; 16). Furthermore experimental manipulation of CaM levels affects progression through the G1 and M-phases, interferes with DNA replication and influences cellular growth and proliferation (17-20). CaM and extracellular Ca2+ levels have been linked to the cell cycle machinery through the phosphorylation state of Rb (21). Rb is a tumor suppressor that is phosphorylated by cyclin-dependent kinases Cdk4 and Cdk2 leading to its dissociation from E2F and the induction of genes required for the G1-S transition (22). Consistent with the effects of CaM on the cell cycle, inhibition of CaMKII results in defects in the G2-M and G1 phases (23). Furthermore, expression of a constitutively active CaMKII arrests the cell cycle in G2 (24). In yeast mutants defective in CaM exhibit defects in progression through mitosis (25-28).
The most clearly defined function for Ca2+ signal during cell cycle transitions is following fertilization of vertebrate eggs. Following maturation vertebrate eggs arrest at metaphase of meiosis II until fertilization. This arrest is mediated by cytostatic factor (CSF) which maintains Cdk1 activity at high levels and thus prevents the activation of the anaphase-promoting complex (APC/C) and the transition to anaphase (29). Fertilization leads to dramatic Ca2+ transient that activates CaMKII (30). CaMKII in turn phosphorylates the APC/C inhibitor Emi2 (31-33). Emi2 phosphorylated by CaMKII becomes a substrate for phosphorylation by polo-like kinase. Dual phosphorylation of Emi2 targets it for degradation by the proteasome thus releasing APC/C inhibition and releasing the metaphase II arrest (34).
The Ca2+-CaM-dependent phosphatase calcineurin has also been implicated in the release of the metaphase II arrest and the activation of the anaphase promoting complex/cyclosome (APC/C) during the meiotic cell cycle (35; 36). Calcineurin inhibition has also been reported to arrest the cell cycle in G1 (37). Furthermore, calcineurin play a central role in the resumption of the cell cycle following antigen stimulation in T-cells. Antigen stimulation activates Ca2+ influx through soce leading to a sustained transient which activates the phosphatase calcineurin (38). Calcineurin dephosphorylate the transcription factor NFAT leading to its translocation to the nucleus and the transcription of genes required for T-cell clonal expansion.
Together these effects show that Ca2+ signaling is pervasive during the cell cycle, through downstream Ca2+-dependent signaling modules that regulate various aspects of cell cycle transition and cellular proliferation. This raises interesting questions about how specificity is achieved to modulate different aspects of the cell cycle through Ca2+ signals. Are specific Ca2+ signaling pathways implicated differentially during different stages of the cycle? Is soce involved and does it play defined roles in cellular proliferation?
3. DIVERSITY OF CA2+ SIGNALING
As discussed above, Ca2+ signals and downstream Ca2+-dependent effectors play important roles during cell proliferation, however it seems that the dependency on Ca2+ signals is defined in a cell type and developmental stage specific fashion (2; 39). Ca2+ signals maintain specificity despite their ubiquitous nature and involvement in disparate cellular behaviors often in the same cell. The attribute of Ca2+ signals that endow them with such versatility is the specific signature encoded in their spatial, temporal and amplitude dynamics (3; 40). This Ca2+ code, coupled to the affinity and association and dissociation constants of downstream Ca2+ binding proteins allows Ca2+ signals to activate distinct signal transduction pathways based on the need of the cell. Spatially, Ca2+ signals can localize to within a few nanometer at the mouth of a channel, and as such activate Ca2+-binding proteins in the immediate vicinity of the channel (41). Alternatively Ca2+ waves can sweep through the entire cell or groups of coupled cells (42). Similarly, temporally Ca2+ signals can be very short lived on the order of mseconds during vesicular exocytosis, or they can persist for quite a long time as illustrated by the Ca2+ oscillations that last up to several hours after fertilization in mammals (43).
The regulation of Ca2+ signaling depends on different channels, transporters and pumps that localize to the cell, mitochondria and ER membranes. The ER constitutes the primary intracellular Ca2+ storage organelle. Free Ca2+ is highest in the extracellular space (1-2mM) and ranges between 250-600 mM in the lumen of the ER (44). In the cytoplasm Ca2+ is maintained at low levels ~100nM to allow signaling to occur. In effect, the extracellular and intracellular Ca2+ pools are functionally linked through the store-operated Ca2+ entry (soce) pathway. Depletion of Ca2+ stores following agonist-induced Ca2+ release, results in Ca2+ influx at the cell membrane. Several of these Ca2+ signaling pathway could be differentially involved in generating the Ca2+ signals required for progression through different stages of the cell cycle. For example, Ca2+ release through the IP3 receptor has been exclusively implicated in the resumption of the meiotic cell cycle during fertilization of the frog egg (45). In the following sections we discuss what is currently known about the role of soce during cellular development and proliferation.
4. STORE-OPERATED CA2+ ENTRY (SOCE)
Soce represents a ubiquitous Ca2+ influx pathway that is pronounced in non-excitable but also present in excitable cells such as skeletal muscle (46; 47). Soce is activated following store depletion in response to activation of G-protein or tyrosine kinase coupled receptors, which activate PLC resulting in inositol 1,4,5 trisphosphate (InsP3) production leading to ER Ca2+ release. Soce is not due to Ca2+ release per se or other PLC-dependent downstream messengers, since it can be induced by store depletion mechanisms that are PLC-independent such as inhibition of endoplasmic reticulum Ca2+-ATPase using thapsigargin (46). Soce is critical for several physiological functions including activation of immune cells and skeletal muscle development (48). As discussed above, following antigen stimulation of T-cells, Ca2+ influx through soce is important for T-cell clonal expansion by initiating re-entry into the cell cycle. Antigens crosslink T-cell receptors leading to PLCg activation and the production of InsP3. InsP3 gates the InsP3-receptor Ca2+ channel on the ER membrane, thus releasing Ca2+ and inducing store depletion, which stimulate Ca2+ influx through soce. This produces a sustained Ca2+ transient, which is required for calcineurin activation and dephosphorylation of NFAT (nuclear factor of activated T cells) (38; 49).
The molecular players mediating soce have been elucidated and studied extensively over the past five years. Large scale RNAi screens identified stromal interaction molecule 1 (STIM1) as the ER Ca2+ sensor (50; 51), and Orai1 as the soce Ca2+ channel at the cell membrane (52-54). STIM1 is a single pass trans-membrane domain protein with a luminal EF-hand allowing it to detect ER Ca2+ content. Orai1 is an integral membrane protein with four trans-membrane domains and cytoplasmic N- and C-termini. Co-expression of STIM1 and Orai1 replicates the biophysical properties of Ca2+-release activated Ca2+ current (ICRAC), which is the best characterized soce current biophysically (54-56). Furthermore, mutations of glutamate residues in the first and second trans-membrane domains confirm that Orai1 lines the soce channel pore as they alter soce current selectivity and permeation (57-59). Finally, mutations in STIM1 and Orai1 in human patients and knock-out strains of either protein in mice abrogate soce in cells of the immune system and other cells in the body (48; 52). Besides STIM1 and Orai1, mammalian genomes encode an additional STIM homologue, STIM2, and two additional Orai genes, Orai2 and 3 (60; 61). In addition to their roles in soce, STIM and Orai proteins are involved in other Ca2+ signaling pathways such as the arachidonate-regulated Ca2+ channel (ARC) (62; 63). STIM1 has also been implicated in the regulation of TRP channels (64).
Structure-function studies on STIM1 and Orai1 have greatly improved our understanding of the coupling mechanism between Ca2+ store depletion and Ca2+ influx at the cell membrane. We will briefly summarize STIM1-Orai1 coupling here since this topic is addressed in significant details in other reviews in this issue. When lumenal Ca2+ levels in the ER fall below a certain threshold Ca2+ dissociates from the STIM1 EF-hand inducing a conformational change in the protein that results in its clustering. Large STIM1 clusters, referred to as puncta, are stabilized in a cortical ER domain within a few nanometers of the cell membrane where they directly interact with Orai1 leading to its co-clustering and gating (53; 57; 59; 65-69). Therefore direct physical coupling between STIM1 -the ER Ca2+ sensor- and Orai1 -the Ca2+ channel at the cell membrane- results in functional coupling between Ca2+ levels in the ER lumen and Ca2+ influx. In addition to its coupling to Orai1, STIM1 also interacts with and gates members of the TRPC channel family (64; 70; 71), which may play a role in cellular proliferation.
5. STIM1 AND ORAI1 DURING THE CELL CYCLE
It has been know for many years that soce inactivates during the division phase of the cell cycle (72). That is in both mitosis of mammalian cells and meiosis of frog oocytes, store depletion does not activate Ca2+ influx (73-76). Recent studies have shown that uncoupling of store depletion from Ca2+ influx during M-phase is due to the inability of STIM1 to cluster in response to depletion of Ca2+ stores (77; 78), and to internalization of Orai1 (77; 79). Orai1 is removed from the cell membrane and becomes enriched in endosomes during Xenopus oocyte meiosis. This occurs by targeting Orai1 for internalization through a caveolin and Rab5-dependent endocytic pathway (79). Combined STIM1 clustering inhibition and Orai1 internalization uncouple Ca2+ store depletion from Orai1 gating, thus inactivating soce. This is the only known physiological situation where soce is inhibited arguing for an important functional role. soce inactivation during cell division may reflect the tight regulation of Ca2+ signaling necessary to ensure proper transition through M-phase. Cell division encompasses dramatic changes to the cell, including the breakdown of the nuclear envelope, chromosome condensation, fragmentation of the Golgi apparatus and remodeling of the cell's cytoskeleton. As discussed above Ca2+ signals have been implicated during various stages of cell division. Hence, soce inactivation may be a mechanism to prevent unwanted Ca2+ influx, which could derail Ca2+-dependent processes during critical stages of M-phase. For the Xenopus egg sporadic Ca2+ influx through soce is likely to lead to egg activation prior to fertilization, which will result in its demise. The fully mature Xenopus egg is arrested at metaphase of meiosis II and is activated by a sweeping Ca2+ wave following sperm fusion (45; 80). A localized Ca2+ transient, as would be mediated by soce activation, is prone to produce a sweeping Ca2+ wave that will activate the egg, including the completion of meiosis in the absence of sperm (81). In fact simply pricking the egg in Ca2+ containing medium is sufficient to activate it (82).
In addition to soce other Ca2+ signaling pathways are also remodeled during cell division, which reflects specific signaling requirements during M-phase. Inositol (1,4,5)-trisphosphate (InsP3)-dependent Ca2+ release is sensitized during both meiosis (83-85) and mitosis (86); and the plasma-membrane Ca2+-ATPase is internalized during meiosis (87; 88).
6. STIM AND ORAI LOSS OF FUNCTION IN ANIMAL MODELS AND HUMANS
The identification of STIM1 and Orai1 as the molecular mediators of soce allows the analysis of the global function of these proteins. Indeed several whole animal and tissue specific knockout strains have been generated and their phenotypes characterized. The generation of STIM1-KO mice produces animals that mostly die either in utero or in the first hours/days of life (89-92), and the few surviving animals have a growth retardation phenotype (89; 93). The cause of the premature death of the animals is not clearly understood yet, with the most obvious phenotype being a respiratory failure in STIM1-KO mice due to severe skeletal muscle dysfunction (89; 91). STIM2-KO mice had a better survival rate (death occurring after 4 to 8 weeks), though they did also exhibit a growth retardation phenotype (90; 93; 94). Whether these growth phenotypes are linked to defects in cellular proliferation is presently not known. Knocking down STIM1 does not significantly affect immune system development, although splenomegaly was reported as well as a lymphoproliferative disease and infiltration of lymphocytes in non lymphoid tissue such as lung and liver. This phenotype is also observed in conditional T-cell restricted STIM1/2 double KO but is not yet fully understood, although it most likely involves the density/function of Treg cells (90; 93).
In the case of Orai1, although Orai1 knockout leads to perinatal death, some mice lacking the channel protein were able to grow providing special breeding or backcrossing conditions but show reduced size, a hair loss phenotype and a deficit in lymphocytic function (95; 96). The proliferation of B-cells following stimulation with an anti-IgM was impaired in Orai1-/- (95). In the case of T-cells the effect of Orai1 deletion does not affect the development of naïve T-cell (96). The phenotype of these knockout lines may not be representative of acute knockdown of Orai1 as expression of other Orai proteins, Orai2 and 3, may complement part of the Orai1 function in lymphocytes and other tissues (95; 96).
The consequences of Orai1 or STIM1 deficiency in humans has been recently reviewed (48; 97). Briefly, patients lacking STIM1 or Orai1 functional genes display a severe immunodeficiency linked, but not restricted, to a reduced T-cell ability to proliferate and to release cytokines. The vulnerability to infections associated with a congenital myopathy strongly limits the survival of patients. In addition, some patients show lymphoproliferative symptoms, a phenotype also observed in STIM1 and STIM1/2 KO mice. Surprisingly, although STIM1 and Orai1 are quite ubiquitously expressed, their absence does not induce a total loss of function in many cell types, suggesting a compensation mechanism involving for instance STIM2 and Orai2 and 3.
Loss of function phenotypes of STIM1 and Orai1 in mice and humans confirm the central role of these proteins in the context of soce in the proliferation of immune cells in response to antigen stimulation. They also show that soce is not essential for the development and differentiation of immune cells. More detailed analyses of different cell types in these knockout models is warranted to better define the role of STIM and Orai1 in cell cycle progression and cell proliferation.
7. VASCULAR SMOOTH MUSCLE AND ENDOTHELIAL CELLS
In vascular smooth muscle cells (VSMC), although SOCE has been recorded for quite some time, the molecular partners contributing to the generation of the calcium current are still a matter of debate. Recently, different strategies aimed at inactivating Orai1 and STIM1 in VSMCs provided new clues to functionally define SOCE in these cells. Knocking down Orai1 but not Orai2 or 3 reduces store-operated calcium influx and current. Moreover, silencing of Orai1 reduces cell proliferation but also cell migration during wound healing in culture (98; 99). Similar results were obtained in cultured VSMCs derived from pulmonary or coronary artery and aorta following the knock-down of STIM1, where both SOCE and VSMCs proliferation were reduced (99-102). The existence of a link between STIM1/Orai1 and cell proliferation is also supported by the finding that proliferating VSMCs have higher expression levels of both proteins (99; 102). Furthermore, siRNA mediated knockdown of STIM1 in VSMC results in G0-G1 arrest (101). This was coupled to increased expression of the CDK inhibitor p21 and an accumulation of the hypo-phosphorylated form of Rb. This would explain the G1 arrest and inability of the cells to progress to S-phase.
Two nuclear targets have been proposed so far to explain the regulation of cellular proliferation by SOCE. First, activation of SOCE by thapsigargin has been shown to induce the phosphorylation of CREB, while knocking down STIM1 reduces the amount of pCREB (100). Second, thapsigargin induced activation of NFAT was strongly reduced by the knockdown of STIM1 as well as production of the mRNA coding for the modulatory calcineurin protein 1 (MCPI1), an NFAT-driven gene (102). Finally, and in contradiction with the previously cited works, it was reported that in VSMCs isolated from the human saphenous vein, the knockdown of STIM1 reduces SOCE without affecting cell proliferation. Conversely, in those cells, the inactivation of TRPC1 reduced cell migration and proliferation (103).
The importance of SOCE in cell proliferation within the vascular system is not restricted to VSMCs. Although the players underlying SOCE in endothelial cells remain controversial (104; 105), STIM and Orai1 proteins have been shown to regulate endothelial cell proliferation. In human umbilical vein endothelial cells in culture, silencing Orai1 increased the proportion of cells in phase S and G2-M. A similar but much lower effect was observed with STIM1 or 2 knockdown, suggesting that Orai1 might act, at least partly, independently of STIM proteins (104). These results also argue that the role of soce in modulating the cell cycle of endothelial cells differ from that of VSMCs. In endothelial precursor cells derived from rat bone marrow, STIM1 levels have been shown to increase during cell proliferation induced by hepatocyte growth factor (106), while STIM1 knockdown limited the proliferation of naïve and stimulated cells (106; 107). These observations are supported in a vascular injury model using balloon angioplasty in rat carotid arteries. After arterial injury, STIM1 expression increases in smooth muscle cells in the media of the injured vessel but also in the neointima, confirming the increased expression of STIM1 in proliferating cells (101). Consistently, knockdown of STIM1 using adenoviral delivery of shRNA and siRNA prevents neointima formation and restores normal lumen diameter (101; 102).
In contrast, STIM1 knockdown in HEK cells in culture has been reported to have no effect on cellular proliferation. siRNA-mediated Orai1 knockdown in HEKs decreases cell proliferation, as does STIM2 knockdown but to lowers level than Orai1 (108). Serum starvation of HEK cells or pharmacological inhibition of cdk1 results in decreased Orai1 protein without affecting RNA levels arguing for translational control of Orai1 expression under these conditions. Therefore the effects of STIM1 knockdown appear to display a cell-type specific effect on cellular proliferation.
8. CANCER CELLS
STIM1 was originally isolated as a tumor suppressor and was termed GOK (109), linking it to cell proliferation and cancer. STIM1 was shown to be expressed in normal skeletal muscle but not in the muscle-derived rhabdomyosarcoma and rhadbdoid tumor cell lines. Moreover, in those cell lines, restoration of STIM1 induces cell death. This tumor suppressive phenotype of STIM1 was shown to be cell-type specific since it was not observed in the breast cancer cell line HBL100 (109). More recently, increased understanding of the structure and function of STIM and Orai proteins, has rekindled interest in the role of SOCE in various cancers, particularly in the case of breast cancer.
Orai1 expression is increased in breast cancer tissue and in the cancer cell line MCF-7 as compared to normal human mammary epithelial cells and to the non-cancerous cell line MCF-10A (110; 111). Knockdown of Orai3 inhibits the proliferation of MCF-7 cells and produces an arrest in G1 phase. A detailed analysis of the key proteins regulating the G1 and G1-S transition revealed that the expression of cyclin D1 and E was decreased as well as their corresponding Cdks (Cdk4/2). At the same time, over-expression of the CDK inhibitor p21Waf1/Cip1 and of the tumor suppressor p53 were observed (110). However it appears that breast cancer cell lines are not homogenous regarding STIM/Orai expression, and can be divided into al least two distinct pools: estrogen receptor-positive cells that express STIM1/2 and Orai3, and estrogen receptor-negative cells that express STIM1 and Orai1 (111).
The knockdown of Orai1 has been shown to reduce the proliferation of MCF-7 but also to reduce tumor generation and inhibit metastasis in mice (112; 113). Conversely, the knockdown of STIM1 did not affect the proliferation of the MCF-7 (112) or of the cell line MDA-MB-231 while reducing serum induced cell migration (114). Adding to the complexity of the pattern, it was also found that Orai1 knockdown can reduce tumor generation and proliferation of the MCF-7 cell line, but that this was independent of STIM1/2 expression and activation. Orai1 has been shown in that case to form a complex with the Secretory Pathway Ca2+-ATPase (SPCA2) to trigger a store-independent calcium influx promoting tumorogenesis (112).
The implication of modulating STIM and Orai protein levels in other types of cancerous cell lines has also been reported although the data are limited to date. In human hepatoma cells, the knockdown of either STIM1, Orai1 or TRPC6 decreases SOCE and cyclin D1 levels (115). In human prostate cancer cells, STIM1/Orai1-dependent SOCE is a major contributor to calcium-induced apoptosis and the expression of Orai1 depends on expression of the androgen receptor, making androgen-independent cells more resistant to apoptosis (116). Although much more remains to be learned about the role of STIM and Orai in cancers it is clear that they are involved in cancer development and metastasis, with the added complexity that their specific role in different types of cancer appears to be cell-type specific.
9. PERSPECTIVES
Over the past few years we have learned significantly about the basic molecular mechanisms of STIM1-Orai1 coupling in the context of soce, however our understanding of the contribution of STIM and Orai proteins to cell cycle progression, cellular proliferation and to cell physiology in general remains in its infancy.
Many questions remain. What are the mechanisms underlying the dramatic inhibition of SOCE during the division phase of the cell cycle? Are the effects of Orai and STIM modulation during cellular proliferation linked to soce and if not what are the specific pathways involved? The interaction of Orai1 with SPCA2 illustrates one example where Orai1 functions in an soce independent fashion. Are there other physiological or pathological situations where this is the case, for either STIM or Orai proteins? What determines the cell-type specific differential roles of STIMs and Orais that is already emerging in the literature? It is fair to speculate that additional molecular partners of STIMs and Orais remain to be discovered and that they may modulate the function of these proteins in a cell-type and developmental specific fashion. Recent reports pointing to STIM-independent, Orai-dependent processes suggests that the cellular physiology of these molecules deviates from a simple model of STIM/Orai interaction. This would explain the differential phenotype observed in distinct cell types following modulation of STIM or Orai expression levels. Moreover, the relative viability of STIM1 and Orai1 knockouts tends to suggests that STIM1 and Orai1 are not key players in the normal process of cell division, or that other isoforms of the proteins can fulfill their roles when they are inactivated. In summary, the future promises exciting discoveries regarding the roles of STIMs and Orais in cellular proliferation and their regulation during the cell cycle.
10. ACKNOWLEDGMENTS
The authors are supported by NPRP grants 08-395-3-088 and 08-138-3-050 from the Qatar National Research Fund (QNRF). The statements made herein are solely the responsibility of the authors. Additional support to the Machaca laboratory comes from the Qatar Foundation's biomedical research program (BMRP) to Weill Cornell Medical College is Qatar (WCMC-Q).
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Key Words: STIM, Orai, Cell Division, Cell Proliferation, Review
Send correspondence to: Khaled Machaca, Weill Cornell Medical College Qatar, PO Box 24144, Education City, Qatar Foundation, Doha, Qatar, Tel: 974-4492-8423, Fax: 974-4492-8422, E-mail:khm2002@qatar-med.cornell.edu