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- Title
Regulation of c-myc expression by IFN-γ through Stat1-dependent and -independent pathways.
- Authors
Ramana, Chilakamarti V.; Grammatikakis, Nicholas; Chernov, Mikhail; Nguyen, Hannah; Kee Chuan Goh; Williams, Bryan R. G.; Stark, George R.
- Abstract
Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that involves regulation of c-myc expression. IFN-γ 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-γ. A role for Raf-1 in the Stat1-independent pathway is revealed by studies with geldanamycin, an HSPg0-specific inhibitor, and by expression of a mutant of p50cdc37 that is unable to recruit HSP90 to the Raf-1 complex. Both agents abrogated the IFN-γ-dependent induction of c-myc expression in Stat1-null cells.
- Subjects
INTERFERONS; FIBROBLASTS; TYROSINE; SERINE; PHOSPHORYLATION; MOLECULAR biology
- Publication
EMBO Journal, 2000, Vol 19, Issue 2, p263
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/19.2.263