The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis

Oncogene. 1998 Dec 3;17(22):2811-8. doi: 10.1038/sj.onc.1202393.

Abstract

Expression of the proto-oncogene c-myc stimulates cell proliferation in the presence of the appropriate survival factors and triggers apoptosis in their absence; this dual capacity ensures that cell growth is restricted to the correct paracrine environment and is thereby strictly controlled. Recently our laboratory demonstrated that c-Myc-induced apoptosis requires the CD95 death receptor pathway and that insulin-like growth factor (IGF-1) signalling suppresses this killing. To investigate further the links between c-Myc and IGF-1 pathways in CD95-induced apoptosis, we examined the effects of c-Myc and a downstream IGF-1 survival kinase, Akt, on killing mediated by CD95 and its recruited effector proteins (FADD and caspase-8). Here, we show that c-Myc activation does not exacerbate killing induced by FADD or pro-caspase-8, which narrows the point at which c-Myc exerts its action downstream of the interaction of CD95 with its ligand and upstream of FADD. We show further that activated Akt suppresses CD95-induced apoptosis and that Akt exerts its activity at a point downstream of FADD but upstream of caspase-8. These results restrict the possible mechanisms by which CD95-induced apoptosis is modulated by death signals and survival factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Antibodies / pharmacology
  • Apoptosis* / drug effects
  • Arabidopsis Proteins*
  • Blotting, Western
  • Caspase 8
  • Caspase 9
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Culture Media, Serum-Free
  • Fatty Acid Desaturases / antagonists & inhibitors
  • Fatty Acid Desaturases / genetics
  • Fatty Acid Desaturases / metabolism
  • Mice
  • Plant Proteins / antagonists & inhibitors
  • Plant Proteins / genetics
  • Plant Proteins / metabolism
  • Protein Precursors / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Proto-Oncogene Proteins*
  • Rats
  • Signal Transduction* / drug effects
  • Sirolimus / pharmacology
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Transfection
  • fas Receptor / immunology
  • fas Receptor / metabolism*

Substances

  • Antibodies
  • Arabidopsis Proteins
  • Culture Media, Serum-Free
  • Plant Proteins
  • Protein Precursors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • fas Receptor
  • Tamoxifen
  • afimoxifene
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Casp8 protein, mouse
  • Casp8 protein, rat
  • Casp9 protein, mouse
  • Casp9 protein, rat
  • Caspase 8
  • Caspase 9
  • Caspases
  • Sirolimus