c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines.
We have investigated the mechanism by which deregulated expression of c-Myc induces death by apoptosis in serum-deprived fibroblasts. We demonstrate that Myc-induced apoptosis in low serum is inhibited by a restricted group of cytokines, principally the insulin-like growth factors and PDGF. Cytokine-mediated protection from apoptosis is not linked to the cytokines' abilities to promote growth. Protection from apoptosis is evident in the post-commitment (mitogen-independent) S/G2/M phases of the cell cycle and also in cells that are profoundly blocked in cell cycle progression by drugs. Moreover, IGF-I inhibition of apoptosis occurs in the absence of protein synthesis, and so does not require immediate early gene expression. We conclude that c-Myc-induced apoptosis does not result from a conflict of growth signals but appears to be a normal physiological aspect of c-Myc function whose execution is regulated by the availability of survival factors. We discuss the possible implications of these findings for models of mammalian cell growth in vivo.
Harrington
E A
EA
Biochemistry of the Cell Nucleus Laboratory, Imperial Cancer Research Fund Laboratories, London, UK.
Bennett
M R
MR
Fanidi
A
A
Evan
G I
GI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D008648:Mesoderm / Q000187:drug effects; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013002:Somatomedins / Q000494:pharmacology*; D013936:Thymidine / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D016271:Proto-Oncogene Proteins c-myc; D013002:Somatomedins; D004958:Estradiol; D005047:Etoposide; D003513:Cycloheximide; D013936:Thymidine