Tax Transactivation in the Context of Chromatin

染色质背景下的税收反式激活

• 批准号: 6514661
• 负责人: JENNIFER K. NYBORG
• 金额: $ 27.72万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514661
• 关键词: HeLa cells; acyltransferase; affinity chromatography; chromatin; genetic promoter element; genetic transcription; histones; human T cell leukemia; human T cell lymphotropic virus type 1; neoplasm /cancer genetics; oncoproteins; recombinant DNA; transcription factor; viral leukemogenesis; virus genetics; virus protein

DESCRIPTION: (Adapted from the Investigator's abstract): The human T-cell leukemia virus, type I, is causally linked to a fatal lymphoproliferative disease called adult T-cell leukemia (ATL). The virally-encoded Tax protein appears directly responsible for the creation of an intracellular environment that is permissive to malignant transformation. Tax is critical to the viral life cycle, as it activates HTLV-I transcription following the assembly of multiprotein complexes in the transcriptional control region of the virus. Recent evidence indicates that the Tax-containing promoter complex is responsible for recruitment of the cellular coactivators, CBP/p300, with the subsequent strong activation of viral transcription. CBP and p300 are highly related proteins that belong to a novel class of transcriptional activators that possess histone acetyltransferase (HAT) activity, and appear to play a significant role in gene-specific activation though modulation of chromatin structure. CBP and p300 are both highly pleiotropic proteins that function in virtually all known cellular programs, including development, differentiation, and cell death. Because of their central role in fundamental biological processes, dysregulation of these proteins has been strongly correlated with human disease, including hematologic malignancies. Based on these observations, we hypothesize that the strong Tax dependence on CBP/p300 underlies HTLV-I associated neoplastic transformation of the infected T-cell. Currently, very little is known about the molecular mechanisms of CBP/p300 transcription function. In this application, we propose to investigate the role of CBP/p300 in Tax-mediated transcriptional activation in vitro. We have selected this system, as the Tax-CBP/p300 interaction is among the best characterized of the coactivator-transcription factor interactions to date. We plan to explore CBP-mediated Tax transcriptional activation using chromatin-assembled templates in vitro. Our methods will allow biochemical dissection of the TaxCBP/p300 interactions, and enable evaluation of putative nucleosome and transcription factor modifications that accompany transcriptional activation. Outcomes of the proposed studies may reveal basic aspects of Tax and CBP/p300 function as they pertain to gene regulation, chromatin structure, and leukemogenesis.

描述：(改编自《调查人员摘要》)：人类T细胞 I型白血病病毒与一种致命的淋巴增生性疾病有因果关系 这种疾病被称为成人T细胞白血病(ATL)。病毒编码的Tax蛋白 似乎直接对细胞内环境的创建负责 这是对恶变的许可。税收是病毒传播的关键 生命周期，因为它在组装后激活HTLV-I转录 病毒转录控制区的多蛋白复合体。 最近的证据表明，含税的启动子复合体是 负责招募CBP/P300细胞共激活剂， 随后病毒转录被强烈激活。CBP和p300高度依赖于 属于一类新的转录激活因子的相关蛋白 具有组蛋白乙酰转移酶(HAT)活性，并似乎扮演着一个 染色质调节在基因特异性激活中的重要作用 结构。CBP和p300都是高度多效性的蛋白质，在 几乎所有已知的细胞程序，包括发育、分化、 和细胞死亡。因为它们在基础生物学中的核心作用 过程中，这些蛋白质的失调与 人类疾病，包括血液系统恶性肿瘤。基于这些观察， 我们假设，对CBP/p300的强烈税收依赖是HTLV-I的基础 被感染的T细胞的相关肿瘤性转化。目前，非常 对CBP/p300转录的分子机制知之甚少 功能。 在这个应用中，我们建议研究CBP/p300在 TAX介导的体外转录激活。我们选择了这个系统， 由于Tax-CBP/p300相互作用是最具特点的 到目前为止，共激活子-转录因子的相互作用。我们计划探索 利用染色质组装模板实现CBP介导的Tax转录激活 在试管中。我们的方法将允许对TaxCBP/p300进行生化解剖 相互作用，并使评估假定的核小体和转录 伴随转录激活而来的因子修饰。会议的结果 拟议的研究可能揭示税收和CBP/p300功能的基本方面，因为它们 与基因调控、染色质结构和白血病发生有关。