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Regulation of c‐ myc expression by IFN‐γ through Stat1‐dependent and ‐independent pathways
Author(s) -
Ramana Chilakamarti V.,
Grammatikakis Nicholas,
Chernov Mikhail,
Nguyen Hannah,
Chuan Goh Kee,
Williams Bryan R.G.,
Stark George R.
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.2.263
Subject(s) - biology , transactivation , stat1 , phosphorylation , null cell , microbiology and biotechnology , signal transduction , transfection , cancer research , cell culture , gene expression , gene , biochemistry , genetics
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 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‐γ‐dependent induction of c‐ myc expression in Stat1‐null cells.