Mechanism of HTLV-1 activation of the SRF pathway.

描述（由申请方提供）：人T细胞嗜淋巴细胞病毒I型（HTLV-I）是两种疾病的病原体：HTLV-I相关脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）和成人T细胞白血病（ATL）。病毒的3'端编码一个353个氨基酸，40千道尔顿的磷蛋白，称为Tax。Tax通过调节识别CREB、NF-κ B和SRF启动子元件的转录因子的活性，以某种方式激活病毒和宿主基因的转录。在每种情况下，Tax不仅与转录因子-DNA复合物相互作用，还与相关因子相互作用。例如，Tax与CREB和共激活因子CBP相互作用，导致病毒基因表达。有强有力的证据表明，Tax在ATL患者的病毒肿瘤发生中起关键作用。ATL是一种快速侵袭性和耐化疗的T细胞癌，最终导致患者平均6个月内死亡。据估计，世界上有1000万至2000万人感染HTLV-I，主要通过母乳传播，其次是输血、静脉注射毒品和性接触。一旦患者被诊断患有ATL，患者的生存概率非常小，因为没有已知的癌症治愈方法。实验室研究表明，Tax诱导原代细胞永生化，并导致软琼脂集落和裸鼠肿瘤的形成。该提案的目标是确定SRF转录途径的Tax激活机制。已发表的数据表明，Tax-CREB相互作用对病毒基因表达很重要，Tax-NF-kappaB相互作用对转化表型的维持很重要。我们假设Tax-SRF相互作用对于转化表型的启动是必不可少的。为了了解Tax在SRF途径中的作用，我们将确定Tax激活血清反应元件（SRE）的机制。税务激活的启动子含有SRE必须要求积极的监管机构是积极的和消极的监管机构是不活跃的，这些事件必须发生组成。我们的方法将是检查税收对SRF功能的三个方面的影响：启动子上的基本转录复合物的组装，MAPK途径（正调节器）的活性，以及抑制剂Id（负调节器）的活性。

DESCRIPTION (provided by applicant): Human T cell lymphotrophic virus type I (HTLV-I) is the etiologic agent of two diseases: HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia (ATL). The 3' end of the virus encodes a 353 amino acid, 40 kiloDalton, phosphoprotein known as Tax. Tax activates the transcription of viral and host genes somehow by modulating the activity of transcription factors which recognize the CREB, NF-kappaB, and SRF promoter elements. In each case, Tax not only interacts with the transcription factor-DNA complex but also with associated factors. For example, Tax interacts with both CREB and the coactivator CBP, resulting in viral gene expression. There is strong evidence that Tax plays a critical role in viral oncogenesis in ATL patients. ATL is rapidly aggressive and chemotherapy-resistant T cell cancer, ultimately resulting in the patient's death within an average of 6 months. An estimated 10-20 million people in the world are infected with HTLV-I, and transmission primarily occurs through human breast milk and to a lesser extent, blood transfusions, IV drug use, and sexual contact. Once the patient is diagnosed with ATL, the survival probability of the patient is extremely small since there is no known cure for the cancer. Laboratory studies have shown that Tax induces the immortalization of primary cells and causes the formation of soft agar colonies and tumors in nude mice. The goal of the proposal is to determine the mechanism(s) of Tax activation of the SRF transcription pathway. Published data indicates that the Tax-CREB interactions are important for viral gene expression and that the Tax-NF-kappaB interactions are important for maintenance of the transformed phenotype. We hypothesize that the Tax-SRF interactions are essential for initiation of the transformed phenotype. To understand the role of Tax in the SRF pathway, we will determine the mechanism of Tax activation of the serum response element (SRE). Tax activation of promoters containing an SRE must require that the positive regulators are active and negative regulators are inactive, and the events must occur constitutively. Our approach will be to examine the effects of Tax on three aspects of SRF function: assembly of the basic transcription complex on the promoter, activity of the MAPK pathway (positive regulator), and activity of the inhibitor Id (negative regulator).