The opposing roles of the Akt and c-Myc signalling pathways in survival from CD95-mediated apoptosis.
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.
Rohn
J L
JL
Biochemistry of the Cell Nucleus Laboratory, Imperial Cancer Research Fund, London, UK.
Hueber
A O
AO
McCarthy
N J
NJ
Lyon
D
D
Navarro
P
P
Burgering
B M
BM
Evan
G I
GI
D016475:3T3 Cells; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D029681:Arabidopsis Proteins; D015153:Blotting, Western; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010940:Plant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D029681:Arabidopsis Proteins; D016895:Culture Media, Serum-Free; D010940:Plant Proteins; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D019014:fas Receptor; D013629:Tamoxifen; C016601:afimoxifene; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020123:Sirolimus