Deregulation of Cellular IkB Kinases by HTLV1 Tax

描述（由申请方提供）：人T细胞白血病病毒1型（HTLV 1）感染可导致不适当的生长信号转导、细胞周期控制的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HTLV 1 Tax癌蛋白与转录因子NF-κ B的相互作用，这通常有助于启动炎症和免疫的遗传程序。与由促炎介质如肿瘤坏死因子-α（TNF）引起的NF-kB作用的瞬时模式相反，NF-kB在表达Tax的细胞中是组成性活性的。Tax通过与IKK（一种TNF诱导的IkB激酶）形成稳定的复合物来劫持这一宿主信号传导途径。反过来，Tax将IKK转化为组成型活性激酶，其指定NF-κ B的细胞质抑制剂用于蛋白水解破坏。这是一个项目的继续申请，以剖析IKK的税收行动的病理机制。在本资助期间进行的研究表明，这一机制涉及税收诱导的IKK磷酸化和泛素化。这两个翻译后修饰是生物化学偶联的。此外，泛素（Ub）与IKK的Tax依赖性缀合在表达YopJ（一种抑制NF-κ B信号转导的Ub样蛋白质蛋白酶）的细胞中被破坏。研究的中心假设是IKK泛素化在正常和病理生理性NF-κ B信号转导的调节中起着关键作用。为了验证中心假设，提出了实验来确定（i）IKK中的Ub受体位点，其响应于Tax癌蛋白和促炎激动剂而被修饰，（ii）IKK的生化机制和功能， NF-kB信号转导中的遍在蛋白化，以及（iii）IKK遍在蛋白化在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参与IKK泛素化的新分子靶点，用于癌症，炎症和自身免疫的治疗干预。 本应用程序的工作范围是对项目公告PA-03-145的响应，标题为“调节疾病过程的遍在蛋白和遍在蛋白样修饰”。

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".