CHROMATIN ACTIVATION IN RETINOID-INDUCED APOPTOSIS

视黄醇诱导的细胞凋亡中的染色质激活

• 批准号: 6188792
• 负责人: PETER J DAVIES
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188792
• 关键词: acetylation; apoptosis; beta galactosidase; chromatin; enzyme activity; gene targeting; genetic promoter element; genetic regulatory element; genetically modified animals; histogenesis; histones; laboratory mouse; protein glutamine gamma glutamyltransferase; retinoid binding proteins; retinoids

Retinoids are metabolites of vitamin A that have profound effects on the growth, differentiation and death (apoptosis) of normal and neoplastic cells. While a lot has been learned of the mechanisms by which retinoids regulate cellular proliferation and differentiation remarkably little is known about the molecular mechanisms involved in retinoid - induced apoptosis. To address this problem, we were recently awarded an RO1 grant (CA76088) to investigate the signaling pathways involved in retinoid-induced apoptosis. These studies were designed to identify the retinoid receptors and signaling pathways (direct versus indirect effects) involved in the induction of the enzyme tissue transglutaminase in cells undergoing apoptosis in vivo. At the time this application was submitted it was not possible to investigate the molecular mechanism of these effects because little was known of the post-receptor mechanisms that linked ligand binding to transcriptional activation. In the interim however important progress has been made in this field with the discovery (based in part on the collaborating investigators findings) that ligand activation of retinoid receptors recruits proteins with histone acetyl transferase activity to the promoter of target genes. It has been hypothesized that alterations in chromatin structure secondary to histone acetylation may be an important contributor to the ligand - dependent activation of transcription. The experimental evidence in support of this hypothesis have been largely gathered in model systems. The goal of the studies included in this proposal will be to determine whether retinoid - dependent acetylation of chromatin contributes to the activation of gene expression in cells undergoing retinoid-induced apoptosis. The proposed studies will address two specific aims. The first will be to characterize retinoid -induced changes in chromatin structure in myeloid leukemia cells undergoing retinoid-induced apoptosis in vitro. The second aim will be to examine the effects of retinoids on chromatin structure in cells undergoing apoptosis during regression of the interdigital webs in vivo. The results of both of these studies should provide novel information on the role of historic acetylation and de-acetylation in cells undergoing apoptosis in vitro and in vivo.

类视黄素是维生素A的代谢产物，对正常和肿瘤细胞的生长，分化和死亡（凋亡）具有深远影响。 尽管已经了解了许多机制，即类视视视感素调节细胞增殖和分化的机制知之甚少，这对类维生素性诱导的凋亡所涉及的分子机制知之甚少。 为了解决这个问题，我们最近被授予RO1赠款（CA76088），以研究类维生素性诱导的凋亡所涉及的信号传导途径。 这些研究旨在鉴定与体内凋亡细胞中酶组织转丁胺酶诱导诱导酶的酶转丁胺酶诱导的视网膜样受体和信号传导途径（直接与间接作用）。 在提交该应用时，不可能研究这些作用的分子机制，因为对将配体结合与转录激活联系起来的受体后机制知之甚少。 在此领域中，在此领域取得了重要的进展，该发现（部分是基于合作研究者发现），即类维生素类动物受体的配体激活募集具有组蛋白乙酰基转移酶活性到靶基因启动子的蛋白质。 已经假设，继发于组蛋白乙酰化的染色质结构的改变可能是转录的依赖性激活的重要原因。 支持该假设的实验证据已在模型系统中大部分收集。 本提案中包括的研究的目的是确定类维生素类染色质的依赖性乙酰化是否有助于在接受类维生素类动物诱导的细胞凋亡的细胞中基因表达的激活。 拟议的研究将针对两个具体目标。第一个是表征类维生素类动物诱导的髓样白血病细胞中染色质结构的变化，并在体外受到了类维生素类动物诱导的凋亡。 第二个目的是检查性类视黄素对体内数字间局部回归期间细胞中染色质结构的影响。 这两项研究的结果均应提供有关历史性乙酰化和去乙酰化在体外和体内凋亡的细胞中的作用的新信息。