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

被引:257
作者
Ramana, CV
Grammatikakis, N
Chernov, M
Nguyen, H
Goh, KC
Williams, BRG
Stark, GR
机构
[1] Cleveland Clin Fdn, Dept Mol Biol, Lerner Res Inst, Cleveland, OH 44195 USA
[2] Cleveland Clin Fdn, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44195 USA
[3] Tufts Univ, Sch Med, Dept Physiol, Boston, MA 02111 USA
关键词
c-jun; cell proliferation; geldanamycin; p50(cdc37); PKR;
D O I
10.1093/emboj/19.2.263
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interferons (IFNs) inhibit cell growth in a Stat1-dependent fashion that involves regulation of c-my 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-l 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.
引用
收藏
页码:263 / 272
页数:10
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