The long-term objective of this study is to understand the molecular mechanisms of target gene activation by cAMP stimulation. CAMP stimulates the expression of numerous target genes via the phosphorylation of the cAMP Response Element Binding protein (BREB) at Ser 133. Ser 11 phosphorylation, in turn promotes target gene activation via the recruitment of CREB Binding Protein (CBP). CBP has been proposed to mediate transcriptional induction, in part via its induction, in part via an intrinsic histone acetyl transferase (HAT) activity, and via its association with polymerase II complex. In preliminary studies, I have determined that histone acetylation potentiates activation of a stably integrated but not an episomal somatostatin reporter gene in NIH-3T3 cells stimulated with cAMP. In this proposal, I will test the hypothesis that CBP induces the acetylation of nucleosomes on the somatostatin gene, and that nucleosome acetylation in turn stimulates the gene's transcription.
