Tax Transactivation in the Context of Chromatin

染色质背景下的税收反式激活

• 批准号: 6335344
• 负责人: JENNIFER K. NYBORG
• 金额: $ 24.86万
• 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/6335344
• 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：（改编自研究者的摘要）：人类 T 细胞 I 型白血病病毒与致命的淋巴增殖性疾病有因果关系 称为成人 T 细胞白血病 (ATL) 的疾病。病毒编码的 Tax 蛋白 似乎直接负责细胞内环境的创建 这是允许恶变的。税收对于病毒式传播至关重要 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物。 最近的证据表明，含税启动子复合体是 负责招募细胞共激活剂 CBP/p300， 随后病毒转录的强烈激活。 CBP 和 p300 高度 属于一类新型转录激活剂的相关蛋白质 具有组蛋白乙酰转移酶 (HAT) 活性，并且似乎发挥着 通过染色质调节在基因特异性激活中发挥重要作用 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。由于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。根据这些观察， 我们假设对 CBP/p300 的强烈税收依赖是 HTLV-I 的基础 受感染 T 细胞的相关肿瘤转化。目前，非常 关于 CBP/p300 转录的分子机制知之甚少 功能。 在此应用中，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， 因为 Tax-CBP/p300 相互作用是最具特征的相互作用之一 迄今为止，共激活剂-转录因子的相互作用。我们计划探索 使用染色质组装模板进行 CBP 介导的 Tax 转录激活 体外。我们的方法将允许对 TaxCBP/p300 进行生化解剖 相互作用，并能够评估假定的核小体和转录 伴随转录激活的因子修饰。结果 拟议的研究可能会揭示税收和 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。