Originally published online as doi:10.1189/jlb.0903450 on April 9, 2004
Published online before print April 9, 2004
(Journal of Leukocyte Biology. 2004;76:7-14.)
© 2004
by Society for Leukocyte Biology
On the link between Bcl-2 family proteins and glucocorticoid-induced apoptosis
Wassim Y. Almawi*,1,
Ohannes K. Melemedjian
and
Maroun M. Abou Jaoude
* Al-Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, Arabian Gulf University, Manama, Bahrain;
Department of Biology, American University of Beirut, Lebanon; and
Multi-Organ Transplant Program, St. Georges Hospital, Beirut, Lebanon
1Correspondence: Al-Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 22979, Manama, Bahrain. E-mail: wyalmawi{at}yahoo.co.uk
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ABSTRACT
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As immunosuppressive agents, glucocorticoids (GCs) act by inhibiting the expression of cytokines and adhesion molecules at the transcriptional and post-transcriptional levels. In addition, GCs exerted their effects by modulating apoptosis. In view of the central role of the Bcl-2 family protein in regulating apoptosis, it was tempting to speculate that GCs modulated apoptosis through modulation of the expression of proapoptotic (Bax, Bcl-XS, Bak) and prosurvival (Bcl-2, Bcl-XL, Bcl-w) Bcl-2 family members. Prosurvival Bcl-2 family members in various cell types antagonized GC-induced apoptosis, thereby suggesting a causal relationship between GC-induced apoptosis and Bcl-2 proteins. The antagonism of apoptosis afforded by prosurvival Bcl-2 proteins appeared to be specific for the GCs, as Bcl-2 and Bcl-xL blocked GC-induced apoptosis in T cell hybridomas but did not affect Fas or activation-induced apoptosis. Although it is speculated that GC-induced apoptosis may be mediated through the activation of proapoptotic Bcl-2 proteins, recent findings suggest that this may vary depending on the conditions and the cell types used. The mechanism by which Bcl-2 inhibited GC-induced apoptosis remains uncertain. It was suggested that Bcl-2 acted on outer mitochondrial membranes to preserve their function. Bcl-2 overexpression also inhibited GC-induced apoptotic events, including caspase activation and mitochondrial dysfunction. The cross-talk of the GC receptors with other secondary messengers could lead to modulation of the activity of Bcl-2 proteins through modification of their phosphorylation status, without ruling out the possibility of a physical interaction between activated GR with Bcl-2 proteins.
Key Words: dexamethase • caspases • bax • cytochrome C
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INTRODUCTION
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Glucocorticoids (GCs) are small, lipophilic compounds used in treatment of autoimmune and inflammatory diseases and for preventing transplant rejection [1
, 2
]. Although it is generally accepted that GCs exerted their immunosuppressive and anti-inflammatory effects by inhibiting the expression of proinflammatory cytokines and adhesion molecules [3
], a growing body of evidence suggested that GCs exerted some of their effects through modulation of apoptotic events [4
, 5
]. Whereas the exact mechanism of action of GCs in modulating apoptosis is not fully elucidated, it likely involves modulation of the expression of proapoptotic and prosurvival genes and their products [6
]. This review addresses this aspect of GC action; for review about other aspects of GC effects, the reader is referred to reviews published elsewhere [3
, 7
].
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MODE OF ACTION OF THE GCs
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Owing to their hydrophobic nature and low molecular weight, GCs diffuse into the cytoplasm and bind their inactive cytosolic receptor (GR) in association with heat-shock protein (HSP)-90, which then undergoes structural modification and assumes the zinc finger configuration [8
] (Fig. 1
). The GC-GR complex translocates to the nucleus, where it inhibits the transcription of T cell and monocyte/macrophage cytokine genes directly or indirectly [3
] (Fig. 1)
. The former is mediated by binding of the activated GR complex to DNA sites compatible with the GRE motifs [9
], which are located in the promoter region of cytokine genes [10
]. The latter reportedly involved antagonism of transcription factors, including activated protein-1 and nuclear factor (NF)-
B, required for optimal transcriptional activity, leading to attenuation of downstream transcriptional events [11
].
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Figure 1. Mode of action of the GCs [1
], which diffuse through the lipid bilayer into the cytosol, where [2
] they bind to their inactive cytosolic receptor (GR), thereby leading to dissociation of the two HSP-90 molecules, and [3
] translocation of the GC-GR complex to the nucleus, where it binds DNA on the promoter region of GC-responsive genes on GC-response element (GRE)-like sites, leading to [4
] modulation of downstream transcriptional events.
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This resulted in inhibition of transcription of many cytokine genes such as interleukin (IL)-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-11, IL-12, IL-16, interferon-
, tumor necrosis factor 
(TNF-), macrophage-colony stimulating factor (M-CSF), granulocyte-CSF (G-CSF), CSF-1, and GM-CSF and subsequently, T cell activation [3
, 7
]. In addition to their transcriptional effects, GCs reportedly acted post-transcriptionally by destabilizing cytokine mRNA and through alteration of its half-life [12
, 13
] and by blocking signaling through high-affinity cytokine receptors [14
15
16
] among others.
GCs also acted, at least in part, by inducing and accelerating apoptosis [4
, 5
], which involved modulation of the expression of proapoptotic and prosurvival genes, including Bcl-2, Mcl-1, Bim, and Bax [17
, 18
]. For example, reduction of cell survival in GC-treated T cell hybridomas, immature thymocytes, and activated T cells was via acceleration of proapoptotic signaling mechanisms (see below), which leads to the notion that the effect of GCs on cell survival is through interference with proapoptotic and prosurvival signals [4
, 19
, 20
]. Collectively, this indicates that GCs act at several levels in regulating lymphocyte activation, including inhibition of cytokine expression and modulation of apoptosis.
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APOPTOSIS
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Apoptosis is an evolutionary, conserved process, which plays a central role in the homeostasis and function of immune cells in maintaining adequate cell numbers, in the deletion and removal of unwanted and autoreactive cells and in the removal of lymhoblasts and other proliferating cell clones generated during the course of an immune response [21
, 22
]. Apoptosis is a highly controlled program associated with morphological changes [22
], including membrane blebbing, cytoplasmic/nuclear condensation, chromatin aggregation, and formation of apoptotic bodies [22
]. Two apoptosis mechanisms operate in mammals, which converge on a common pathway involving participation of effector caspases (aspartate-specific cysteine proteases), adaptor molecules including apoptotic protease-activating factor-1 (Apaf-1), and several regulatory molecules, including the Bcl-2 proteins and the inhibitors of apoptosis (IAPs) [21
, 23
]. Caspases are grouped into initiator caspases (caspases 1, 2, 4, 5, 8, 9, 10, 11, and 12) with a long N terminus and effector caspases (caspases 3, 6, 7) with a short prodomain.
Activation of the death receptor apoptosis, exemplified by FasL/Fas/Fas-associated death domain (FADD) and TNF receptor 1 (TNF-R1)/TNF/TNF-R-associated death domain [24
, 25
], is distinct from the second mechanism, apoptosis induced by cytokine withdrawal, p53 activation, or cytotoxic drugs, in many regards. Although not controlled by Bcl-2 proteins [26
], death receptor apoptosis is dependent on activation of a caspase 8-like activity [27
] and hence, is inhibited by FADD-like IL-1ß-converting enzyme (FLICE)-inhibitory proteins [28
]. In contrast, the latter pathway is resistant to the action of FLICE-inhibitory proteins [29
] and is effectively regulated by Bcl-2 proteins (see below) [30
].
In response to external signals imparted by cytokine deprivation, DNA damage, or cytotoxic drugs [31
] or to internal developmental signals (death-by-neglect), inactive apoptotic proteins are activated, leading to the exposure of phosphatidylserine, degradation of vital cellular targets including poly(adenosine 5'-diphosphate-ribose) polymerase, DNA-dependent protein kinase and other substrates [32
, 33
], and eventually leading to DNA degradation and cell death [34
]. Apoptosis is regulated by many cellular factors, some of which promote apoptosis (proapoptotic), and others inhibit it (prosurvival). Aberrant increases in proapoptotic or a decrease in prosurvival proteins [31
] reduce the overall survival of lymphoid/myeloid cells potentially precipitating a state of immunodeficiency, and heightened expression and function of prosurvival proteins enhance lymphoid/myloid cell accumulation.
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Bcl-2 FAMILY
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The Bcl-2 family (B cell leukemia/lymphoma 2-like proteins) is a major regulator of mitochondria-regulated apoptotic events and is a member of a growing gene family consisting of two subfamilies that can inhibit (prosurvival) or promote (proapoptotic) apoptosis [21
]. The interplay between proapoptotic and prosurvival proteins plays a pivotal role in determining the eventual outcome (death or survival). More recently, it was shown that the Bcl-2 (prosurvival)-to-Bax (proapoptotic) ratio in the cell determines to a large extent whether the cell initiates apoptosis or alternatively, re-enters the cell cycle [35
, 36
]. This was exemplified by the finding that overexpression of Bcl-2 (hence, a higher Bcl-2:Bax ratio) allowed for continued cellular proliferation through antagonism of apoptotic signals imparted by the proapoptotic Bax, as seen in the perpetuated growth and division of malignant cells [20
]. Insofar as the Bcl-2 proteins regulated cell survival and in view of the capacity of the GCs to modulate apoptosis, it was suggested that GCs controlled apoptosis by regulating the expression of Bcl-2 proteins.
In excess of 25, Bcl-2 family members were identified in human, of which some inhibited apoptosis (prosurvival) and include Bcl-2, Bfl-1, Boo/Bcl-B, Bcl-xL, Bcl-w, Mcl-1, or promote apoptosis (proapoptotic), members of which include Bax, Bak, Bok/Mtd, Bcl-xS, Bcl-GL, Bad, Bid, Bik/Nbk, Bim/Bod, Blk, Bmf, and Hrk [21
] (Fig. 2
). In some cases, altered splicing of Bcl-2 mRNA into two or more proteins leads to the production of two proteins with opposing effects on cell survival, as with Bcl- xL and Bcl-xS. Certian Bcl-2 proteins (Bcl-2, Bak) are localized in the mitochondria, and others (Bax, Bad, Bid) are cytosolic [37
]. All Bcl-2 proteins are structurally related and consist of a hydrophobic pocket and an amphipathic -helix [38
], a conserved homology region designated as BH domain [37
, 39
], and a TM region (Fig. 2)
. All prosurvival Bcl-2 proteins exhibit sequence homology at BH1, BH2, BH3, and BH4 regions [37
] and are localized to the cytoplasmic faces of cellular membranes (outer mitochondrial, endoplasmic reticulum, and nuclear membranes) [40
, 41
]. Proapoptotic Bcl-2 proteins, although structrurally related to their prosurvival counterparts, exhibit sequence homology at BH1, BH2, and BH3 domains [37
], and a subgroup of the proapoptotic proteins, the BH3-only-containing proteins, share with the others only the short BH3 region. These include Bad, Bcl-Gs, Bid, Bik/Nbk, Bim/Bod, Blk, Bmf, Hrk, and Noxa [21
, 37
].
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Figure 2. Classification and organization of the proapoptotic and prosurvival Bcl-2 family members. BH, Bcl-2 homology; TM, transmembrane.
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Bcl-2 PROTEINS: MECHANISTIC CONSIDERATIONS
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Bcl-2 proteins bind to each other through their respective BH domains, forming homo- and heterodimeric complexes [39
, 40
]. Formation of homodimers of prosurvival Bcl-2 or Bcl-xL involves binding through their BH1 and BH2 domains, and BH3-containing proapoptotic proteins such as Bax or Bak bind prosurvival proteins including Bcl-2 or Bcl-xL [39
] through their BH3 domains [42
]. The ratio between prosurvival and proapoptotic proteins (Bcl-2/Bax) dictates to a large extent the susceptibility or resistance to apoptotic signals, which may be imparted by growth factors [43
], radiation [44
], and anticancer drugs [45
] and frequently, associated with conditions associated with unimpeded cell growth and proliferation or alternatively, with accelerated cell death. These include cancer [46
, 47
], autoimmune disorders [48
], human immunodeficiency virus infection, and ischemia-reperfusion injury [49
].
Whereas prosurvival (Bcl-2) and proapoptotic (Bax) Bcl-2 proteins exhibited sequence and structural similarities, they functionally opposed each other and appeared to regulate apoptosis independently [50
]. Although the exact mechanisms leading to apoptosis are not fully elucidated yet, it is believed that the BH3-only-containing proteins Bad (and Bim), which are phosphorylated by protein kinase A (PKA) and Akt, initiate it. The subsequent translocation of Bax to the mitochondria involves a conformational change that exposes the N- and C-termini [51
], and its complexing with Bak (Bax:Bak) also requires a conformational change in Bak [52
, 53
]. Bax:Bak complex in turn stimulates the release of cytochrome C via a mechanism that may include formation of mitochondrial pores [54
]. Cytochrome C then binds its adaptor, Apaf-1, leading to the activation of caspase 9, which subsequently activates effector caspases leading to cell death [55
]. Prosurvival Bcl-2 reportedly antagonized apoptosis by binding and sequestering BH3-only proteins, thus preventing the formation of Bax:Bak clusters and hence, inhibits downstream apoptotic events such as caspase activation [56
]. Similarly, proapoptotic Bcl-2 proteins (Bim) antagonize prosurvival Bcl-2 proteins by liberating Apaf-1-like adaptor molecules, which in turn activate caspases leading to cell death [57
].
It is also possible that Bcl-2 prevented Bax-induced cytochrome C release by preserving mitochondrial membrane integrity and thus preventing pore formation [36
, 54
]. The cytochrome C/Apaf-1/caspase 9 pathway does not seem to be an obligatory step in apoptosis, as cells devoid of Apaf-1 or cytochrome C can still undergo caspase-mediated apoptosis [58
] and as dexamethasone (DEX)-induced apoptosis of multiple myeloma (MM) cells, although associated with caspase 9 activation, does not depend apriori on cytochrome C/Apaf-1 oligomerization (see below; ref. [59
]). In addition, crossing Bax knockouts with Bcl-2 knockouts demonstrated that a single copy of Bax was capable of promoting apoptosis in the absence of Bcl-2 in thymocytes, and overexpression of Bcl-2 repressed apoptosis in the absence of Bax, suggesting that Bax and Bcl-2 can function independently of one another in vivo to regulate apoptosis [50
].
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REGULATION OF Bcl-2 BY GCs
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Several reports documented the capacity of GCs to regulate the expression of Bcl-2 proteins and modulate apoptosis. Prosurvival members of the Bcl-2 family blocked apoptosis induced by GCs and other stimuli in various cell types, as overexpression of Bcl-2 in human pre-B-lymphocytes [60
] and Mcl-1 and Bcl-2 in MM cells [61
] protected from GC-induced apoptosis. IL-7 reportedly antagonized DEX-induced apoptosis in mature T cells by blocking apoptotic events induced by DEX (effector caspase activation, dephosphorylation of Akt/PKB) and also by elevating IAP levels [62
]. In addition, transfection of the murine lymphoid cell lines, S49.1 and WEHI 7.2 with Bcl-2 [63
] and PC12 cells with Bcl-xL [64
], provided for increased resistance to GC-induced DNA fragmentation. In contrast, Bcl-2 knockout mice displayed accelerated apoptosis of thymocytes in response to DEX [65
]. The antagonism of apoptosis afforded by prosurvival Bcl-2 proteins appeared to be specific for the GCs, as Bcl-2 and Bcl-xL blocked GC-induced apoptosis in T cell hybridomas but did not affect death receptor apoptosis [66
] and as Bcl-2 inhibited GC-induced apoptosis but only partially blocked calcium ionophore or cyclohexamide-regulated apoptosis in the mouse lymphoma S49 cell line [67
].
In addition, GCs promoted apoptosis through induction of the expression of proapoptotic Bcl-2 proteins (Bad) in thymocytes [68
] or through reduction in the expression of prosurvival (Bcl-2 and Bcl-xL) proteins in leukemic cells [31
] and other cell types [69
]. The suppression of prosurvival Bcl-2 members by GCs and abrogation of GC-induced apoptosis by overexpression of Bcl-2 [20
] suggested a causal relationship between GC-induced apoptosis and Bcl-2 proteins via a mechanism, which may require a prerequisite generation of hydrogen peroxide [70
] or altered transmembrane transport (see below).
GCs appeared to differentially regulate the expression of Bcl-2 proteins and apoptotic events depending on the cell type and stimulation condition. Although GCs were ineffective in modulating killing induced by a CD95-independent pathway [71
], they induced monocyte apoptosis by a CD95-dependent signaling pathway, which involved up-regulation and the release of membrane-bound CD95 receptor and ligand [72
]. DEX up-regulated the expression of prosurvival Bcl-xL in parallel with a number of initiator and effector caspases and stimulated apoptosis in osteoblastic cells [73
].
Recently, it was proposed that GC-induced regulation of downstream apoptotic events including regulation of Bcl-2 proteins involves induction of a novel class of GC-regulated proteins (apparently distinct from Bcl-2 family proteins), which in turn modulates downstream apoptotic events. T cell death-associated gene-8 was induced shortly following DEX treatment, and its expression stimulated the activation of caspases 3, 8, and 9 [74
]. In addition, DEX-induced gene 2 was described as a DEX-induced prosurvival protein, which presumably acted by modulating caspase activation [75
].
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GC IMMUNOSUPPRESSION AND Bcl-2 EXPRESSION: OPPOSING VIEWS
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Insofar as GCs profoundly inhibited cytokine production and cellular proliferation [3
, 7
] and induced and accelerated apoptosis [5
] and in view of the central role of Bcl-2 family members in modulating apoptosis, several studies addressed the causal relationship between GC immunosuppression and GC modulation of Bcl-2 proteins. Studies on the human pre-B cell lines 380, which express a high level of Bcl-2, and 697 cells, which expressed a lower level of Bcl-2, showed that although GCs inhibited cellular proliferation and repressed c-myc mRNA expression in both cell lines, GC treatment of the 380 cell line resulted in inhibition of cellular proliferation but no induction of apoptosis, and treatment of the 697 cell line resulted in inhibition of cellular proliferation and apoptosis [60
].
Although it is speculated that GC-induced apoptosis may be mediated through the activation of proapoptotic Bcl-2 family members, recent findings suggest that this may vary depending on the conditions and the cell types used. Based on studies of knockout mice, Bid and Bax were shown not necessary for the induction of thymocyte apoptosis by DEX [76
, 77
], although others pointed to a central role for Bax in mediating DEX-induced apoptosis [17
, 78
]. In addition, Bim deficiency in Bim knockout mice showed that induction of apoptosis in thymocytes was inhibited by DEX [30
]. Furthermore, DEX inhibited apoptosis in fibrosarcoma cells by activating Bcl-xL [79
], and Bcl-xL overexpression did not protect from GC-induced apoptosis in breast cancer cells [78
]. These apparent contradictions are reconciled by differences in cell types used (T cells/thymocytes vs. other cell types) and the stimulation conditions and readout system used. Accordingly, effects of GCs on modulation of apoptosis and Bcl-2 proteins must be discussed in the context of the cell type and activation conditions used.
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GC MODULATION OF Bcl-2 EXPRESSION: MECHANISTIC CONSIDERATION
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GC-induced apoptosis appears to be exacted at several levels, leading to effector caspase activation. DEX enhanced the expression of BH3-only-containing Bim (BimEL, BimL, and BimS), which in turn facilitated the Bax mitochondrial translocation and complexing with Bak [53
] and caspase 9 activation [18
]. GCs also acted by triggering the release of second mitochondria-derived activator of caspases (Smac), which in turn activates caspase 9. The finding that blockade of Smac release conferred DEX resistance on MM cells supported Smac involvement in GC-induced apoptosis [59
]. GCs also acted by altering mitochondrial transmembrane potential to preserve mitochondrial transmembrane function, which subsequently modulated downstream caspase activation. In support of this mechanism was the recent finding that DEX-induced apoptosis of murine thymocytes was antagonized by the polyamine spermine, which presumably acted by blocking DEX-induced reduction in mitochondrial transmembrane potential (see below) and caspase 9 activation [80
]. Furthermore, overexpression of Bcl-2 antagonized GC-induced loss of mitochondrial membrane potential and thus, generation of reactive oxygen species in the pre-B leukemia cell line, 697 [81
].
GCs were described to act more proximal in modulating phosphorylation events associated with apoptosis. DEX-induced caspase 9 activation required activation of phosphatidylinositol-specific phospholipase C and its association with GR-associated src kinase, thereby resulting in caspase 8 activation and subsequently, cytochrome C release and caspase 9 activation [82
]. Others suggested that Bcl-2 functioned upstream of caspases in inhibiting commitment to cell death, suggesting that anatagonism of GC-induced apoptosis imparted by Bcl-2 is not exacted at the level of caspase inhibition [83
]. DEX may also activate caspase 9 independently of cytochrome C:Apaf-1 oligomerization via a mechanism that reportedly involved induction of Smac, which in turn binds IAPs, thereby relieving the inhibitory effect of IAPs on caspase 9 [84
].
Furthermore, the involvement of Bcl-2 in GC-induced apoptosis was described to be at the level of the cell cycle and its regulators, as Bcl-2 overexpression delayed the increase in cyclin-dependent kinase (Cdk)2 activity associated with DEX-induced apoptosis [85
]. This was in contrast to Bax, the overexpression of which enhanced Cdk2 activity [85
]. Bcl-2 promoted survival by regulating proteasome degradation of transcription factors such as c-Fos and NF-B and antagonized DEX-induced degradation of c-Fos by proteasomes [86
]. This did not require interference with the expression of the NF-B antagonist inhibitor of B but rather upstream in the NF-B activation-signaling pathway [87
], possibly by stabilization of NF-B DNA binding through inhibition of its degradation by proteasomes [87
]. This was supported by the finding that overexpression of Bcl-2 in MM cells abrogated DEX-mediated repression of NF-B activity and thus, apoptosis.
Although it is not tested, it is possible that GC-induced apoptosis and BH3-only-containing proapoptotic proteins are linked through 14-3-3 proteins, whereby 14-3-3 proteins sequester Bad, hence preventing its downstream effects on Bax:Bak complexing. According to this model, dissociation of Bad:14-3-3 complex releases Bad, hence stimulating apoptosis [88
]. Previous studies showed that 14-3-3 protein binds the COOH terminus (but not the ligand-binding domain) of the GR, thereby forming a complex [89
, 90
]. Accordingly, GC effects on Bad (and downstream apoptosis) are proximal to caspase activation and do not target proapoptotic Bcl-2 proteins directly but simply result from sequestration of 14-3-3 by GR.
A model, referred to as the rheostat model, proposed to explain the role of heterodimerization, suggests that the amount of (proapoptotic) Bax, which does not heterodimerize with (prosurvival) Bcl-2 or Bcl-xL, determines the apoptotic threshold and hence, cell survival in GC-treated cells. Accordingly, greater amounts of free, uncomplexed Bax precipitate a lower apoptotic threshold [91
], hence the Bax/Bcl-2 ratio associated with sensitivity to DEX, and the ratio appeared to be more important than the Bcl-2 level as a predictor for drug-induced apoptosis [92
].
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SIGNIFICANCE AND RELEVANCE
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Clinical trials highlighted the importance of the Bax-to-Bcl-2 ratio as a prognostic tool for leukemias, and a trial of childhood acute lymphoblastic leukemia showed that neither blast reduction following 1 week of prednisone monotherapy nor long-term, disease-free survival correlated with Bcl-2 family protein expression [93
]. Conversely, although Bcl-2 expression was not associated with increased in vitro drug resistance, increased expression of Bcl-2 at the time of relapse did correlate with increased resistance to GCs [94
]. In addition, Bax mRNA was shown to be comparatively higher in cells from nonprogressive B cell chronic lymphocytic leukemia (B-CLL) patients [95
].
Based on these and other studies, it appears that the Bcl-2/Bax ratio serves a diagnostic and prognostic role, as higher ratios were found in progressive patients, and was found to be important for regulation of cell survival of other types of cells subjected to apoptotic stimuli [96
, 97
]. The Bax protein, if present at higher levels in nonprogressive B-CLL, may counteract the protective effect of the Bcl-2. Although GCs may reduce the mRNA levels of Bcl-2 and Bax in B-CLL cells, the Bcl-2/Bax ratio remained lower than that of the controls [98
].
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CONCLUSION
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It is clear that GCs display a dual effect (stimulation or repression) on the expression of Bcl-2 family members depending on the cell type studied and the experimental system used, which in turn influences several downstream events associated with cell death. However, the mechanisms that regulate the induced modulation of GCs of the Bcl-2 family need to be illustrated. Regulatory mechanisms may involve engagement of its (GRE-like) responsive element, post-transcriptional regulation by transcription, and other factors, dimerization, phosphorylation-dephosphorylation, and protein displacement. Indirect mechanisms were proposed, and these were thought to involve induction of GC-induced mediators, which in turn modulate downstream events [18
, 74
]. The cross-talk of the GC receptors with other secondary messengers could lead to modulation of the activity of the Bcl-2 proteins through modification of their phosphorylation-dephosphorylation status [6
, 82
]. It is also interesting to speculate the possibility of the GR heterodimerizing with the members of the Bcl-2 family.
Received September 30, 2003;
revised December 20, 2003;
accepted February 16, 2004.
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