Abstract
Nuclear factor-κB (NF-κB) 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-κB 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-κB transcription. Knockdown of copine-I by siRNA increases tumor necrosis factor α-stimulated NF-κB transcription, while copine-I expression blocks endogenous transcription. Copine-I abolishes NF-κB transcription by inducing endoprotease processing of the N-terminus of p65, a process antagonized by IκBα. 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-κB transcription. Our work provides evidence that copine-I regulates the half-life of NF-κB transcriptional responses through a novel mechanism that involves endoproteolysis of the p65 protein.
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Acknowledgements
We thank A Sherman and L Gray for editorial assistance. This work was supported by the National Cancer Institute R01CA095644 and R01CA104397 awarded to MWM and the Department of Defense Idea Development Award PC050549 to MWM and CEC.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Ramsey, C., Yeung, F., Stoddard, P. et al. Copine-I represses NF-κB transcription by endoproteolysis of p65. Oncogene 27, 3516–3526 (2008). https://doi.org/10.1038/sj.onc.1211030
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DOI: https://doi.org/10.1038/sj.onc.1211030
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