Coregulatory factor modulation of CREB activity

描述（由申请人提供）：第二信使cAMP调节多种细胞功能中不同基因亚群的表达。该提案的目标是验证这样的假设：环磷酸腺苷介导的基因表达是由含有共激活因子和共抑制因子的蛋白质复合物调节的。这种基因激活模型是当前基因调控模型的延伸，其涉及不同的共激活子和共阻遏子复合物，其中这些复合物的组分是离散的且相互排斥的。我们的初步数据表明，CBP，共激活的CREB结合蛋白，形成一个复合物与共阻遏组蛋白脱乙酰酶（HDAC）。我们的模型提出CREB在被蛋白激酶A磷酸化时招募CBP，这反过来又将HDAC带到CREB/CBP复合物中。我们已经证明CREB在细胞内是乙酰化的，并且CREB的乙酰化增强了CREB的反式激活活性。由于CBP是一种已知的组蛋白乙酰转移酶（HAT），能够乙酰化CREB，我们假设CREB的乙酰化是由CBP和HDAC组成的复合物调节的。本申请中提出的实验集中于理解CREB的乙酰化调节其活性的机制以及HDAC在调节CREB乙酰化中的作用。CREB/CBP系统已经作为一个原型来说明转录因子的磷酸化及其与辅激活子/辅抑制子的相互作用对基因表达调控的影响。从这些研究中获得的知识和见解将对理解转录因子乙酰化在基因转录调控中的作用具有重要意义。

DESCRIPTION (provided by applicant): The second messenger cAMP regulates the expression of distinct subsets of genes in a variety of cell functions. The goal of this proposal is to test the hypothesis that cAMP-mediated gene expression is regulated by a protein complex containing both co-activators and co-repressors. This model of gene activation is an extension of the current model of gene regulation that involves distinct co-activator and co- represser complexes, where the components of these complexes are discrete and mutually exclusive. Our preliminary data show that CBP, the co-activator of the CRE-binding protein CREB, forms a complex with co-repressor histone deacetylases (HDAC). Our model proposes that CREB, when phosphorylated by Protein Kinase A, recruits CBP, which in turn brings HDACs to the CREB/CBP complex. We have shown that CREB is acetylated within the cell, and that acetylation of CREB enhances CREB's transactivation activity. Because CBP is a known histone acetyltransferase(HAT) and is able to acetylate CREB, we hypothesize that acetylation of CREB is regulated by the complex consisting of CBP and HDACs. The experiments proposed in this application focus on understanding the mechanism by which acetylation of CREB regulates its activity and the role of HDACs in regulating CREB acetylation. The CREB/CBP system has served as a prototype to illustrate the effects of phosphorylation of transcription factors and their interaction with co-activators/co-repressors on regulation of gene expression. Knowledge and insights gained from the proposed studies will have important implications for understanding the role of acetylation of transcription factors in the regulation of gene transcription.