CREB-binding protein (CBP) functions as a coactivator for many transcription factors and is able to respond to extracellular signals to specifically regulate gene expression. Mutations within CBP have been found in patients with mental retardation and growth defects (Rubinstein-Taybi syndrome) and have been demonstrated in patients with acute myelogenous leukemia. Several viruses that cause diseases in humans (HTLV-l, HIV-1, CMV, HBV, and adenovirus) also use CBP to regulate gene expression. Regulation of transcription by CBP occurs in part through its ability to function as a histone acetylase transferase (HAT), and in part through contact with other molecules which themselves function as HATs or which function as general transcription factors such as TBP. Recent work indicates that CBP contacts a specific subset of proteins to activate transcription at different promoters. We have identified a novel protein termed SRCAP (SNF2-Related-CBP-Activator Protein) that binds to a region within CBP shown to be important for CBP to function as a coactivator for CREB. SRCAP regulates the ability of CREB and CBP to activate transcription and we have found that SRCAP regulates transcription of several promoters (PEPCK, somatostatin, and enkephalin) that utilize CREB and CBP to activate transcription. In addition, we have found that SRCAP enhances glucocorticoid receptor-mediated transcription of the MMTV-promoter. Recent studies indicate that SRCAP (like CBP) is targeted by several viral proteins. These include: the HCV core protein that inhibits CREB-mediated transcription; the HCV NS5A protein that in conjunction with SRCAP represses transcription of the p21 gene; the adenovirus protein, DBP, that blocks CBP-SRCAP interaction and inhibits transcription mediated by SRCAP; and the adenovirus protein, Ela that binds CBP and blocks binding of CBP to SRCAP. The proposed studies will determine whether interaction of CBP and SRCAP is needed for CREB-mediated transcription of endogenous genes. They will determine the mechanism(s) through which SRCAP activates CREB-mediated transcription and by which SRCAP activates GR-transcription of the MMTV promoter. These studies will also determine whether SRCAP binding proteins regulate the ATPase and transcriptional activities of SRCAP. For example, we have found that the Dead box RNA helicase protein (DBX) binds to SRCAP and represses CREB-mediated transcription. We propose to determine whether this repression of CREB-mediated transcription occurs through formation of a DBX-SRCAP complex.
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