Roles of CBP & PCAF During Hematopoietic Differentiation

描述(申请人提供)：转录因子控制基因 通过募集高分子量蛋白质共激活复合体来表达 基因的调控区域。其中一些复合体含有染色质 修饰酶。一类这样的酶由组蛋白组成 乙酰基转移酶包括广泛表达的分子CBP，它的近似性 相对p300和p300/CBP相关因子PCAF。CBP/P300和PCAF是 病毒癌蛋白干扰分化和分化的关键靶点 促进细胞周期进程。此外，CBP和p300基因是 在染色体易位中重排与某些形式的 白血病。最近的证据表明，CBP/p300和PCAF受 控制细胞生长和分化的信号。 拟议研究的目标是了解CBP和PCAF的作用 在造血细胞分化过程中。造血功能相当于一种 研究血统承诺过程的理想模型系统，细胞 成熟，细胞周期退出。造血转录因子核因子-E2 是红系和巨核细胞基因表达的关键调节因子。我们的 初步研究表明，核因子-E2与CBP结合并被CBP乙酰化 和PCAF。特定目标的实验1检验分子和生物学 核因子-E2乙酰化的后果。我们的初步结果还表明， PCAF蛋白水平在分化过程中受到差异调节 不同的造血细胞谱系。《特定目标2》考察了PCAF的作用 造血细胞分化的调控。此外，这一目标 将分析CBP和PCAF的活动和亚基组成 造血分化过程中的复合体。总而言之，这些研究将 导致对乙酰基转移酶的分子理解的提高 作为各种血液病药物干预的潜在靶点 精神错乱。

DESCRIPTION (provided by applicant): Transcription factors control gene expression by recruiting high molecular weight protein coactivator complexes to the regulatory regions of genes. Some of these complexes contain chromatin modifying enzymes. One class of such enzymes consists of histone acetyltransferases which includes the widely expressed molecules CBP, its close relative p300, and the p300/CBP-associated factor PCAF. CBP/p300 and PCAF are critical targets of viral oncoproteins which interfere with differentiation and promote cell cycle progression. In addition, the CBP and p300 genes are rearranged in chromosomal translocations associated with certain forms of leukemia. Recent evidence suggests that CBP/p300 and PCAF are regulated by signals that control cell growth and differentiation. The goal of the proposed studies is to understand the roles of CBP and PCAF during the differentiation of hematopoietic cells. Hematopoiesis serves as an ideal model system in which to study the processes of lineage commitment, cell maturation, and cell cycle exit. The hematopoietic transcription factor NF-E2 is a key regulator of erythroid and megakaryocytic gene expression. Our preliminary studies show that NF-E2 associates with and is acetylated by CBP and PCAF. Experiments in Specific Aim 1 examine the molecular and biological consequences of NF-E2 acetylation. Our preliminary results also indicate that PCAF protein levels are differentially regulated upon differentiation of distinct hematopoietic cell lineages. Specific Aim 2 examines the role of PCAF regulation during hematopoietic cell differentiation. Furthermore, this Aim will analyze the activities and subunit compositions of the CBP and PCAF complexes during hematopoietic differentiation. Together, these studies will lead to an improved molecular understanding of acetyltransferases which stand as potential targets for pharmacological intervention in various hematological disorders.