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

Eur J Immunol. 1998 Jan;28(1):57-69. doi: 10.1002/(SICI)1521-4141(199801)28:01<57::AID-IMMU57>3.0.CO;2-8.

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 p70S6K represents the relevant downstream target of PI 3-kinase signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Arabidopsis Proteins*
  • COS Cells
  • Chromones / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Fas Ligand Protein
  • Fatty Acid Desaturases / physiology*
  • HL-60 Cells
  • Humans
  • Leukemia, T-Cell / pathology
  • Mast-Cell Sarcoma / pathology
  • Membrane Glycoproteins / immunology*
  • Mice
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Plant Proteins / physiology*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Transfection
  • Wortmannin
  • fas Receptor / immunology*

Substances

  • Androstadienes
  • Arabidopsis Proteins
  • Chromones
  • Enzyme Inhibitors
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Faslg protein, rat
  • Membrane Glycoproteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Plant Proteins
  • Proto-Oncogene Proteins
  • fas Receptor
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin