Tax Transactivation in the Context of Chromatin

描述：（改编自研究者摘要）：人T细胞 白血病病毒，I型，与致命的淋巴增生性 成人T细胞白血病（ATL）病毒编码的Tax蛋白 似乎直接负责细胞内环境的创造 这是允许恶性转化。税收对病毒至关重要 生命周期，因为它激活HTLV-I转录后组装 在病毒的转录控制区的多蛋白复合物。 最近的证据表明，含Tax的启动子复合物是 负责募集细胞共激活因子CBP/p300， 随后强烈激活病毒转录。CBP和p300是非常重要的。 属于一类新的转录激活因子的相关蛋白质 具有组蛋白乙酰转移酶（HAT）活性，并似乎发挥作用， 通过染色质调节在基因特异性激活中重要作用 结构CBP和p300都是高度多效性的蛋白质， 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 这些蛋白质的失调与以下过程密切相关： 人类疾病，包括血液恶性肿瘤。根据这些观察， 我们假设HTLV-I的基础是对CBP/p300的强烈税收依赖 相关的肿瘤转化的受感染的T细胞。目前，非常 CBP/p300转录的分子机制目前还知之甚少 功能 在本申请中，我们建议研究CBP/p300在以下方面的作用： Tax介导的体外转录激活。我们选择了这个系统， 由于Tax-CBP/p300相互作用是最具特征的相互作用之一 共激活因子-转录因子相互作用。我们计划探索 利用染色质组装模板的CBP介导的Tax转录激活 体外我们的方法将允许生化解剖的TaxCBP/p300 相互作用，并能够评估推定的核小体和转录 伴随转录激活的因子修饰。成果 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。

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.