Protection of CD95-mediated apoptosis by activation of phosphatidylinositide 3-kinase and protein kinase B.
Apoptosis may be triggered, in a variety of tissues, by interaction of the cell surface molecule CD95 with its specific ligand, CD95L. CD95 plays a physiological role in the regulation of the immune response; furthermore, alterations in CD95/CD95L function may contribute to the pathogenesis of a number of human diseases, including cancer, autoimmune diseases and viral infections. Many cells that express CD95, however, are not susceptible to CD95-mediated apoptosis. It is therefore important to identify the mechanisms that counteract the CD95 apoptotic process that are still poorly understood. Growth factors and lymphokines such as interleukin (IL)-4 that counteract CD95-mediated apoptosis may activate phosphatidylinositide 3-kinase (PI 3-kinase). We therefore used two different approaches to investigate the role of PI 3-kinase on CD95-mediated apoptosis. First we tested the effect of two pharmacological PI 3-kinase inhibitors, wortmannin and LY294002, on CD95 agonistic antibody-induced apoptosis in three different cell lines. Second, we co-expressed in COS7 cells CD95 with constitutively active PI 3-kinase. Results of both approaches indicate that active PI 3-kinase effectively protects against CD95-mediated apoptosis. Furthermore we extended our studies on the CD95 downstream mediator, FADD, and on the PI 3-kinase downstream mediator, the serine/threonine protein kinase PKB, using the co-expression approach in COS7 cells. We provide evidence that apoptosis induced by triggering the CD95 cell death receptor is counteracted by PI 3-kinase activation; moreover, PKB but not p70S6K represents the relevant downstream target of PI 3-kinase signaling.
Häusler
P
P
Department of Immunobiology, Institute of Cell Biology, National Research Council, Rome, Italy.
Papoff
G
G
Eramo
A
A
Reif
K
K
Cantrell
D A
DA
Ruberti
G
G
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D029681:Arabidopsis Proteins; D019556:COS Cells; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D044943:Fatty Acid Desaturases / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D015458:Leukemia, T-Cell / Q000473:pathology; D012515:Mast-Cell Sarcoma / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014162:Transfection; D000077191:Wortmannin; D019014:fas Receptor / Q000276:immunology*
D000730:Androstadienes; D029681:Arabidopsis Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D044943:Fatty Acid Desaturases; D008562:Membrane Glycoproteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010940:Plant Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D019014:fas Receptor; C505661:FASLG protein, human; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C084083:Fad7 protein, Arabidopsis