Regulation of c-myc expression by IFN-γ through Stat1-dependent and -independent pathways

Chilakamarti V. Ramana, Nicholas Grammatikakis, Mikhail Chernov, Hannah Nguyen, Kee Chuan Goh, Bryan R.G. Williams, George R. Stark

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238 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)263-272
Number of pages10
JournalThe EMBO Journal
Volume19
Issue number2
DOIs
Publication statusPublished - 17 Jan 2000
Externally publishedYes

Keywords

  • c-jun
  • Cell proliferation
  • Geldanamycin
  • P50(cdc37)
  • PKR

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