Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways.
Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that involves regulation of c-myc expression. IFN-gamma suppresses c-myc in wild-type mouse embryo fibroblasts, but not in Stat1-null cells, where IFNs induce c-myc mRNA rapidly and transiently, thus revealing a novel signaling pathway. Both tyrosine and serine phosphorylation of Stat1 are required for suppression. Induced expression of c-myc is likely to contribute to the proliferation of Stat1-null cells in response to IFNs. IFNs also suppress platelet-derived growth factor (PDGF)-induced c-myc expression in wild-type but not in Stat1-null cells. A gamma-activated sequence element in the promoter is necessary but not sufficient to suppress c-myc expression in wild-type cells. In PKR-null cells, the phosphorylation of Stat1 on Ser727 and transactivation are both defective, and c-myc mRNA is induced, not suppressed, in response to IFN-gamma. A role for Raf-1 in the Stat1-independent pathway is revealed by studies with geldanamycin, an HSP90-specific inhibitor, and by expression of a mutant of p50(cdc37) that is unable to recruit HSP90 to the Raf-1 complex. Both agents abrogated the IFN-gamma-dependent induction of c-myc expression in Stat1-null cells.
Ramana
C V
CV
Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Grammatikakis
N
N
Chernov
M
M
Nguyen
H
H
Goh
K C
KC
Williams
B R
BR
Stark
G R
GR
D000818:Animals; D000077214:Becaplermin; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D016259:Genes, myc / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D010982:Platelet-Derived Growth Factor; D016271:Proto-Oncogene Proteins c-myc; D020574:Proto-Oncogene Proteins c-sis; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D000077214:Becaplermin; D016899:Interferon-beta; D007371:Interferon-gamma