Deregulation of Cellular IkB Kinases by HTLV1 Tax

HTLV1 税对细胞 IkB 激酶的放松管制

• 批准号: 7073491
• 负责人: DEAN BALLARD
• 金额: $ 42.22万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073491
• 关键词: I kappa B beta; autoimmune disorder; biological signal transduction; chemical fingerprinting; cytokine; enzyme activity; gene induction /repression; gene mutation; genetically modified animals; helper T lymphocyte; human T cell lymphotropic virus type 1; inflammation; laboratory mouse; mass spectrometry; molecular site; nuclear factor kappa beta; oncoproteins; phosphorylation; protein binding; protein protein interaction; serine threonine protein kinase; site directed mutagenesis; ubiquitin; virus infection mechanism; virus protein

DESCRIPTION (provided by applicant): Infection with human T-cell leukemia virus type 1 (HTLV1) can lead to inappropriate growth-signal transduction, the loss of cell cycle control, and the development of an aggressive malignancy manifested as adult T-cell leukemia (ATL). Acquisition of the transformed phenotype is contingent upon the interplay of the HTLV1 Tax oncoprotein with transcription factor NF-kB, which normally helps initiate the genetic programs for inflammation and immunity. In contrast to the transient pattern of NF-kB action elicited by proinflammatory mediators such as tumor necrosis factor-alpha (TNF), NF-kB is constitutively active in cells expressing Tax. Tax hijacks this host signaling pathway by forming stable complexes with IKK, a TNF-inducible IkB kinase. In turn, Tax converts IKK into a constitutively active kinase that earmarks cytoplasmic inhibitors of NF-kB for proteolytic destruction. This is an application for continuation of a project to dissect the pathologic mechanism of Tax action on IKK. Studies conducted during the present funding period indicate that this mechanism involves Tax-induced phosphorylation and ubiquitination of IKK. These two post-translational modifications are biochemically coupled. Moreover, Tax-dependent conjugation of ubiquitin (Ub) to IKK is disrupted in cells expressing YopJ, a Ub-like protein protease that inhibits NF-kB signal transduction. The central hypothesis under investigation is that IKK ubiquitination plays a critical role in the regulation of both normal and pathophysiologic NF-kB signaling. To test the central hypothesis, experiments are proposed to determine (i) the Ub acceptor sites in IKK that are modified in response to the Tax oncoprotein and proinflammatory agonists, (ii) the biochemical mechanism and function of IKK ubiquitination in NF-kB signal transduction, and (iii) the in vivo role of IKK ubiquitination in Tax-associated disease and immunobiology. Results from these studies may facilitate the identification of new molecular targets involved in IKK ubiquitination for therapeutic intervention in cancer, inflammation, and autoimmunity. The workscope of this application is responsive to Program Announcement PA-03-145, entitled "Ubiquitin and ubiquitin-like modifications regulating disease processes".

描述（由申请人提供）：人类 T 细胞白血病病毒 1 型 (HTLV1) 感染可导致不适当的生长信号转导、细胞周期控制丧失以及表现为成人 T 细胞白血病 (ATL) 的侵袭性恶性肿瘤的发展。转化表型的获得取决于 HTLV1 Tax 癌蛋白与转录因子 NF-kB 的相互作用，这通常有助于启动炎症和免疫的遗传程序。与肿瘤坏死因子-α (TNF) 等促炎介质引起的 NF-kB 作用的瞬时模式相反，NF-kB 在表达 Tax 的细胞中具有组成型活性。 Tax 通过与 IKK（一种 TNF 诱导型 IkB 激酶）形成稳定复合物来劫持该宿主信号通路。反过来，Tax 将 IKK 转化为一种组成型活性激酶，指定 NF-kB 的细胞质抑制剂进行蛋白水解破坏。这是一项继续项目的申请，旨在剖析 IKK 税收行动的病理机制。目前资助期间进行的研究表明，该机制涉及税收诱导的 IKK 磷酸化和泛素化。这两种翻译后修饰是生化偶联的。此外，泛素 (Ub) 与 IKK 的税务依赖性缀合在表达 YopJ 的细胞中被破坏，YopJ 是一种抑制 NF-kB 信号转导的 Ub 样蛋白蛋白酶。正在研究的中心假设是 IKK 泛素化在正常和病理生理 NF-kB 信号传导的调节中发挥着关键作用。为了检验中心假设，建议进行实验以确定（i）IKK 中响应 Tax 癌蛋白和促炎激动剂而被修改的 Ub 受体位点，（ii）IKK 的生化机制和功能 NF-kB 信号转导中的泛素化，以及 (iii) IKK 泛素化在 Tax 相关疾病和免疫生物学中的体内作用。这些研究的结果可能有助于识别 IKK 泛素化所涉及的新分子靶点，以用于癌症、炎症和自身免疫的治疗干预。 该应用程序的工作范围响应于题为“调节疾病过程的泛素和泛素样修饰”的计划公告 PA-03-145。