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