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Papers In Press, published online ahead of print May 5, 2003
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655-0106
Corresponding Author: andre.vanwijnen{at}umassmed.edu
Cell growth control by interferons (IFNs) involves upregulation of the tumor suppressor Interferon Regulatory Factor 1 (IRF1). To exert its anti-proliferative effects, this factor must ultimately control transcription of several key genes that regulate cell cycle progression. Here we show that the G1/S phase related cyclin dependent kinase 2 (CDK2) is a novel proliferation-related downstream target of IRF1. We find that IRF1, but not IRF2, IRF3 or IRF7, selectively represses CDK2 gene transcription in a dose- and time-dependent manner. We delineate the IRF1-responsive repressor element between nt -68 to -31 of the CDK2 promoter. For comparison, the tumor suppressor p53 represses CDK2 activity independently of IRF1 through sequences upstream of nt -68, and the CDP-cut/Cux1 homeodomain protein represses transcription downstream of -31. Thus, IRF1 repression represents one of three distinct mechanisms to attenuate CDK2 levels. The -68/-31 segment lacks a canonical IRF responsive element but contains a single SP1 binding site. Mutation of this element abrogates SP1 dependent enhancement of CDK2 promoter activity as expected, but also abolishes IRF1 mediated repression. Forced elevation of SP1 levels increases endogenous CDK2 levels, while IRF1 reduces both endogenous SP1 and CDK2 protein levels. Hence, IRF1 represses CDK2 gene expression by interfering with SP1 dependent transcriptional activation. Our findings establish a causal series of events that functionally connect the anti-proliferative effects of interferons with the IRF1 dependent suppression of the CDK2 gene, which encodes a key regulator of the G1/S phase transition.
J. Biol. Chem, 10.1074/jbc.M301491200
Submitted on February 11, 2003
Revised on May 5, 2003
Accepted on May 5, 2003
The tumor suppressor IRF1 interferes with SP1 activation to repress the human CDK2 promoter
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