Exploring How HTLV-1 Tax Induces T Cell Leukemia

探索 HTLV-1 税如何诱导 T 细胞白血病

• 批准号: 6769460
• 负责人: Warner C. Greene
• 金额: $ 36.52万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769460
• 关键词: I kappa B beta; amidohydrolases; biological signal transduction; cAMP response element binding protein; genetically modified animals; human T cell leukemia; human T cell lymphotropic virus type 1; laboratory mouse; nuclear factor kappa beta; p53 gene /protein; phosphorylation; transcription factor; viral carcinogenesis; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): The type I human T cell leukemia virus (HTLV-I) is a complex type C retrovirus etiologically linked with several diverse human diseases including: (1) the Adult T Cell Leukemia (ATL), an aggressive and usually fatal neoplastic expansion of activated CD4+ T lymphocytes; (2) Tropical Spastic Paraparesis/HTLV-I associated myelopathy (TSP/HAM), a progressive neurodegenerative process involving the spinal cord; and (3) a variety of poorly understood autoimmune or inflammatory diseases that affect different end organs including the eye, salivary glands, joints, and muscle. The molecular basis for HTLV-I transformation of human CD4+ T lymphocytes remains unclear, however, the pX-encoded Tax gene product appears to play a central role. Tax both enhances viral replication and deregulates the expression of various host cell genes by altering the activity of select host transcription factors including NF-kappaB/Rel and CREB/ATF. To define the molecular events associated with full T cell transformation, we will utilize Tax expressing transgenic mice that develop T-cell lymphomas closely resembling ATL. Transgenic animals expressing mutants of Tax that are selectively impaired for NF-kappaB/Rel or CREB/ATF dependent gene expression will be evaluated to define the role played by each of these individual transcription factor pathways in T cell transformation. We will further assess the requirement for continuous Tax or NF-kappaB/Rel expression for maintenance of Tax induced tumors by preparing and studying transgenic animals conditionally expressing Tax or a nondegradable mutant of IkappaBalpha that potently inhibits NF-kappaB/Rel activation by Tax (Specific Aim 1). In a second line of study, we will explore how Tax activates the NF-kappaB/Rel family of transcription factors, following its physical assembly with the IKKgamma subunit of the signalsome complex. The potential recruitment of upstream kinases to the signalsome by Tax and the potential role of Tax oligomerization will be assessed. In related studies, we will test whether the inactivation of the p53 tumor suppressor by Tax involves phosphorylation by the IKK complex. (Specific Aim 2). In a third line of experimentation, we will investigate how Tax induces the sustained, long-term nuclear expression of NF-kappaB, which differs sharply from transient response elicited by physiological stimuli. We will specifically examine whether Tax subverts the generation of negative signals within the IKK complex that normally terminates signalsome action. Additionally, we will explore the potential interplay of Tax with a newly recognized negative pathway of nuclear NF-kappaB regulation involving deacetylation of RelA by histone deacetylase 3. Such deacetylation promotes the rapid nuclear export of RelA and contributes to termination of the NF-kappaB response (Specific Aim 3). Through these combined in vivo and in vitro experiments, we hope to gain key insights into the molecular events underlying HTLV-I Tax mediated leukemogenesis.

描述（由申请人提供）：I型人类T细胞白血病病毒（HTLV-I）是一种复杂的C型逆转录病毒，该病毒在病因上与几种多样化的人类疾病联系起来，包括：（1）成人T细胞白血病（ATL），一种积极的且通常是致命的肿瘤性肿瘤性的肿瘤性肿瘤，可激活的CD4+ T lymphopphopphocpytes; （2）热带痉挛性模拟/HTLV-I相关的骨髓病（TSP/HAM），这是一种涉及脊髓的进行性神经退行性过程； （3）各种各样的自身免疫性或炎症性疾病，这些疾病影响了不同的端口器官，包括眼睛，唾液腺，关节和肌肉。人CD4+ T淋巴细胞的HTLV-I转化的分子基础尚不清楚，但是，PX编码的税收基因产物似乎起着核心作用。税收既可以增强病毒复制，又通过改变宿主转录因子的活性（包括NF-kappab/rel和creb/atf）的活性来消除各种宿主细胞基因的表达。为了定义与全T细胞转化相关的分子事件，我们将利用表达转基因小鼠的税收，这些小鼠与ATL非常相似。将评估对NF-kappab/rel或creb/atf依赖基因表达有选择性损害的税收突变体的转基因动物，以定义T细胞转化中这些单个转录因子途径中每个单个转录因子途径的作用。我们将进一步评估通过准备和研究有条件地表达税收或不可分解的ikappabalpha突变体的转基因动物来维持税收诱发肿瘤的持续税或RER表达的要求，从而用不良的ikappabalpha进行了严厉抑制NF-kappab/rel celm activation ta Tax ta Tax ta Tage ta Tax（特定目标1）。在第二次研究中，我们将探讨税收如何激活转录因子的NF-kappab/rel家族，因为它与信号综合体的ikkgmama亚基进行了物理组装。通过税收和税收低聚的潜在作用，上游激酶的潜在募集将评估。在相关研究中，我们将测试通过税收抑制p53肿瘤是否涉及IKK复合物磷酸化的失活。 （特定目标2）。在第三行实验中，我们将研究税收如何诱导NF-kappab的持续长期核表达，这与生理刺激引起的短暂反应截然不同。我们将专门研究税收是否颠覆了通常终止信号动作的IKK综合体内的负面信号的产生。此外，我们将探索涉及组蛋白脱乙酰基酶脱乙酰基的核NF-kappab调节的新认识的负面途径的潜在相互作用。这种脱乙酰基化促进了Rela的快速核出口，并为NF-Kappab响应的终止有助于（特定的AIM AIM 3）。通过这些结合的体内和体外实验，我们希望能够对HTLV-I税收介导的白血病的基础事件获得关键见解。