Signaling pathways involved in glucocorticoid-induced apoptosis of thymocytes.
This review synthesizes recent insights on the signaling pathways triggered by glucocorticoids during apoptosis of thymocytes. Thymocyte apoptosis is a complex process, which is involved in thymic selection. Even if the main partners are identified, there still remain dark zones on the whole pathway and notably on the crosstalk between each signaling cascade. Glucocorticoids trigger thymocyte apoptosis by enhancing cyclin-dependent kinase 2 activity, downregulating the expression of antiapoptotic Bcl-2 proteins, and upregulating that of proapoptotic Bcl-2 proteins. These events result in mitochondrial alterations and subsequent caspase activation. Proteasome intervenes at various levels of the signaling cascades--for instance, degrading the glucocorticoid receptor or caspase inhibitory proteins. Changes in intracellular K+ and Ca2+ concentrations are involved in caspase and endonulease activation. All these effects are dependent on macromolecular synthesis. The only known non-genomic effect of glucocorticoids is an early production of sphingolipids (ceramide and sphingosine), which are involved in caspase activation independent of mitochondrial alterations. Externalization of phosphatidylserine, a process mediating phagocytosis of dying thymocytes, depends on pathways that diverge from those leading to nuclear apoptosis.
Lépine
Sandrine
S
Biomembranes et Messagers Cellulaires, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Université Paris XI-Orsay, France.
Sulpice
Jean-Claude
JC
Giraud
Françoise
F
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013107:Sphingolipids / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*
D005938:Glucocorticoids; D019253:Proto-Oncogene Proteins c-bcl-2; D013107:Sphingolipids