Copine-I: Modulator of NF-kappa B Transcription and Prostate Cancer Survival

The purpose of our studies is to elucidate how Copine-I antagonizes NF-.B transcription. Nuclear factor-.B NF-.B 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-.B 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-.B transcription. Knockdown of Copine-I by siRNA increases tumor necrosis factor a-stimulated NF-.B transcription, while Copine-I expression blocks endogenous transcription. Copine-I abolishes NF-.B transcription by inducing endoprotease processing of the N-terminus of p65, a process antagonized by I.Ba. 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-.B transcription. Our work provides evidence that Copine-I regulates the half-life of NF-.B transcriptional responses through a novel mechanism that involves endoproteolysis of the p65 protein. Copine has significance as a potential biomarker for therapeutic intervention in prostate cancer.