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Oncogene. 2008 Jun 5;27(25):3516-26. doi: 10.1038/sj.onc.1211030. Epub 2008 Jan 21.

Copine-I represses NF-kappaB transcription by endoproteolysis of p65.

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1
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.

Abstract

Nuclear factor-kappaB (NF-kappaB) is a dynamic transcription factor that regulates important biological processes involved in cancer initiation and progression. Identifying regulators that control the half-life of NF-kappaB is important to understanding molecular processes that control the duration of transcriptional responses. In this study we identify copine-I, a calcium phospholipid-binding protein, as a novel repressor that physically interacts with p65 to inhibit NF-kappaB transcription. Knockdown of copine-I by siRNA increases tumor necrosis factor alpha-stimulated NF-kappaB transcription, while copine-I expression blocks endogenous transcription. Copine-I abolishes NF-kappaB transcription by inducing endoprotease processing of the N-terminus of p65, a process antagonized by IkappaB alpha. Copine-I stimulates endoproteolysis of p65 within a conserved region that is required for base-specific contact with DNA. p65 proteins lacking the N-terminus fail to bind to DNA and act as dominant-negative molecules that inhibit NF-kappaB transcription. Our work provides evidence that copine-I regulates the half-life of NF-kappaB transcriptional responses through a novel mechanism that involves endoproteolysis of the p65 protein.

PMID:
18212740
DOI:
10.1038/sj.onc.1211030
[Indexed for MEDLINE]
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