On the link between Bcl-2 family proteins and glucocorticoid-induced apoptosis.
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-X(S), Bak) and prosurvival (Bcl-2, Bcl-X(L), 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-x(L) 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.
Almawi
Wassim Y
WY
Genetics and Inherited Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 22979, Manama, Bahrain. wyalmawi@yahoo.co.uk
Melemedjian
Ohannes K
OK
Jaoude
Maroun M Abou
MM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D005938:Glucocorticoids / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology*
D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2