Roles of CBP & PCAF During Hematopoietic Differentiation

CBP 的角色

• 批准号: 6430130
• 负责人: Gerd A Blobel
• 金额: $ 29.92万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6430130
• 关键词: DNA binding protein; acetylation; acyltransferase; cell cycle; cell differentiation; cell growth regulation; chromatin; enzyme activity; enzyme inhibitors; erythroid stem cell; gene expression; genetic regulation; hematopoiesis; hematopoietic stem cells; protein structure function; tissue /cell culture; transcription factor

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.

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因子复合物来表达 基因的调控区。其中一些复合物含有染色质 修饰酶其中一类酶由组蛋白 乙酰转移酶，包括广泛表达的分子CBP，其接近 相对p300和p300/CBP相关因子PCAF。CBP/p300和PCAF是 干扰分化的病毒癌蛋白的关键靶点， 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受以下因素的调节： 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 在造血细胞的分化过程中。造血作为一种 理想的模型系统，其中研究谱系承诺的过程，细胞 成熟和细胞周期退出。造血转录因子NF-E2 是红系和巨核细胞基因表达的关键调节因子。我们 初步研究表明，NF-E2与CBP结合并被CBP乙酰化 和PCAF。具体目标1中的实验检查了分子和生物学 NF-E2乙酰化的后果。我们的初步结果还表明， PCAF蛋白水平在分化成 不同的造血细胞谱系。具体目标2审查了太平洋武装部队的作用 在造血细胞分化过程中的调节。此外，这一目标 将分析CBP和PCAF的活性和亚基组成 在造血分化过程中的复合物。这些研究将 导致对乙酰转移酶分子理解的提高， 作为药物干预各种血液学疾病的潜在靶点， 紊乱