Fas-mediated apoptosis in T cells involves the dephosphorylation of the retinoblastoma protein by type 1 protein phosphatases.
Apoptosis is triggered by a number of different stimuli including the activation of Fas antigen, a member of the TNF family, by the Fas ligand. The signal transduction events implicated in apoptosis are complex and remain only partially understood. In this study, we used calyculin A, a potent inhibitor of serine/threonine (ser/thr) phosphatases types 1 and 2A, to investigate the role of ser/thr phosphatases in Fas-induced apoptosis. We showed that calyculin A inhibited Fas-induced DNA fragmentation and cytolysis in Jurkat cells and that this inhibition was not due to the modulation of Fas. Okadaic acid also inhibited Fas-induced apoptosis of Jurkat cells, but at much higher concentrations (microM level), thus implicating that type 1 phosphatases rather than type 2A are inhibited at nM concentrations. Cross-linking Fas led to the dephosphorylation of the retinoblastoma gene product (Rb) within 5 min, and to PARP cleavage within 2 h. Both events were inhibited by calyculin A indicating that apoptotic death triggered by Fas cross-linking involves the activation of type 1 ser/thr phosphatases.
N'cho
M
M
Department of Microbiology-Immunology, Indiana University School of Medicine, Indianapolis 46202-5200, USA.
Brahmi
Z
Z
D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008387:Marine Toxins; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D011506:Proteins; D016160:Retinoblastoma Protein; D019014:fas Receptor; C059041:calyculin A; D010749:Phosphoprotein Phosphatases