Coregulatory factor modulation of CREB activity

描述(由申请人提供)：第二信使cAMP在各种细胞功能中调节不同的基因亚集的表达。这项提议的目的是检验一种假设，即cAMP介导的基因表达受到包含共激活因子和共抑制因子的蛋白质复合体的调控。这种基因激活模型是当前基因调控模型的扩展，该模型涉及不同的共激活和共抑制复合体，其中这些复合体的组成部分是离散的和相互排斥的。我们的初步数据表明，CBP是CRE结合蛋白CREB的共同激活剂，与共同抑制因子组蛋白脱乙酰酶(HDAC)形成复合体。我们的模型认为，当CREB被蛋白激酶A磷酸化时，会招募CBP，进而将HDAC带到CREB/CBP复合体中。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，我们推测CREB的乙酰化受CBP和HDAC组成的复合体的调控。本申请中提出的实验侧重于了解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，阐明了转录因子的磷酸化及其与共激活/共抑制因子的相互作用对基因表达调控的影响。从拟议的研究中获得的知识和见解将对理解转录因子的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.