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PMID: 10637230 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 19 ·No. 2 ·2000-01-17 ·Pages 263-72

Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR

Abstract

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.

MeSH Terms
Animals Becaplermin DNA-Binding Proteins/metabolism Embryo, Mammalian Fibroblasts/physiology Gene Expression Regulation/drug effects,physiology Genes, Reporter Genes, myc/immunology Humans Interferon-beta/pharmacology Interferon-gamma/pharmacology Mice Platelet-Derived Growth Factor/pharmacology Proto-Oncogene Proteins c-myc/genetics Proto-Oncogene Proteins c-sis Recombinant Fusion Proteins/biosynthesis Recombinant Proteins/pharmacology STAT1 Transcription Factor Signal Transduction Trans-Activators/metabolism Transfection Tumor Cells, Cultured
Chemicals
DNA-Binding Proteins Platelet-Derived Growth Factor Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins c-sis Recombinant Fusion Proteins Recombinant Proteins STAT1 Transcription Factor STAT1 protein, human Stat1 protein, mouse Trans-Activators Becaplermin Interferon-beta Interferon-gamma
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Ramana C V
Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Grammatikakis N
Chernov M
Nguyen H
Goh K C
Williams B R
Stark G R
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.2.263
Published
2000-01-17
Pages
263-72
Language
English
Region
England
NLM ID
8208664
PMCID
PMC305560
Subset
IM
Grants
NCI NIH HHS · P01 CA062220 · United States
NCI NIH HHS · P01 CA62220 · United States
External Links
PubMed source DOI: 10.1093/emboj/19.2.263 PMC Full Text View journal details
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