Regulatory Mechanisms in Transcriptional Signaling

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DESCRIPTION (provided by applicant): Transcriptional regulation plays a fundamental role in specifying cellular and tissue differentiation, cell growth, development and susceptibility to diseases. The highly regulated process of eukaryotic gene expression is coordinated by the interplay of multiple mechanisms involving chromatin, transcription factors such as nuclear hormone receptors and critical accessory/regulatory proteins with histone/chromatin modifying activities. Histones undergo posttranslational modifications such as acetylation, phosphorylation and methylation. These modified histones subsequently led to the establishment of a "histone code" of transcription. For example, unmodified histones repress transcription while acetylated histories promote gene activation. The mechanisms by which unmodified histones "code" for transcriptional repression in higher eukaryotes are largely unknown. Post-translational modification of coregulators also influence gene transcription. The long-term goal of our research is to identify and molecularly characterize novel mechanisms regulating hormonal signaling and transcription. We have recently shown that a human cellular complex termed INHAT regulates nuclear receptor function and transcription at least in part by binding to histones and modulating histone acetyltransferase activity of coactivators, pp32 is a subunit of the INHAT complex and a nuclear phosphoprotein. We hypothesize that pp32 is a critical component in transcriptional repression and that phosphorylation of pp32 plays a critical role in its in vivo function. To test the hypotheses we will (1) determine the role ofpp32 in translating the repressive "histone code" of transcription; (2) characterize molecular mechanisms of transcriptional repression by pp32; and (3) analyze the role of phosphorylation in pp32 function in vivo. We will address the above specific aims using a combination of in vitro and in vivo analyses involving biochemical, molecular, and cell biological methodologies. Altered activities of proteins regulating histone modifications and protein phosphorylation have been linked to altered hormone signaling and human diseases including cancer, and developmental abnormalities. The information stemming from the proposed studies should not only provide a better understanding of transcription and hormone signaling but may also be useful in targeted drug development to treat human diseases.