Protection of CD95-mediated apoptosis by activation of phosphatidylinositide 3-kinase and protein kinase B

Peter Häusler, Giuliana Papoff, Adrians Eramo, Karin Reif, Doreen A. Cantrell, Giovina Ruberti

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)

Abstract

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 p70(S6K) represents the relevant downstream target of PI 3-kinase signaling.

Original languageEnglish
Pages (from-to)57-69
Number of pages13
JournalEuropean Journal of Immunology
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 1998

Keywords

  • Apoptosis
  • CD95
  • Phosphatidylinositide 3-kinase
  • Protein kinase B

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