REGULATION OF SOMATOSTATIN GENE EXPRESSION

Salk Institute For Biological Studies, La Jolla CA

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Abstract

Cyclic AMP stimulates the expression of numerous genes via the PK-A[unreadable] mediated phosphorylation of CREB at Ser133. Ser133 phosphorylation in turn[unreadable] regulates CREB activity by promoting complex formation with the signal[unreadable] dependent co-activators CBP and P300. CBP/P300 have been proposed to[unreadable] mediate transcriptional activation via their association with RNA[unreadable] polymerase II, and via intrinsic histone acetyl transferase activities[unreadable] that may counteract the repressive effects of promoter bound nucleosomes.[unreadable] The proposed studies focus on the mechanism by which cellular signals[unreadable] regulate complex formation between CREB and CBP, and on the mechanism by[unreadable] which CBP-associated HAT activities promote expression of cAMP responsive[unreadable] genes. The functional importance of contact residues in CREB and CBP for[unreadable] transcriptional activation will be evaluated and additional phospho-[unreadable] acceptor sites in CREB which regulate CREB:CBP complex formation will be[unreadable] characterized. The functional importance of CBP-HAT activity for[unreadable] transcriptional activation by phospho (Ser133) CREB will also be examined[unreadable] by expressing wild-type and HAT defective CBP polypeptides in CBP -/-[unreadable] cells. Finally, the mechanism by which histone deacetylase inhibitors[unreadable] synergize with cAMP to promote accumulation of target gene transcripts[unreadable] will be examined. Do cellular HAT activities stimulate assembly of the[unreadable] transcriptional apparatus via chromatin remodeling? Based on recent[unreadable] observations indicating a central role for CREB in learning and memory,[unreadable] the information gained from these studies may contribute importantly to[unreadable] our understanding of diseases which impair cognitive function.[unreadable]