Deregulation of Cellular IkB Kinases by HTLV1 Tax

描述(申请人提供)：感染人类T细胞白血病病毒1型(HTLV1)可导致不适当的生长信号转导，失去细胞周期控制，并发展为表现为成人T细胞白血病(ATL)的侵袭性恶性肿瘤。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，转录因子通常有助于启动炎症和免疫的遗传程序。与促炎症介质如肿瘤坏死因子-α(TNFa)诱导的一过性核因子-kB的作用模式不同，核因子-kB在表达TAX的细胞中具有结构性的活性。Tax通过与IKK形成稳定的复合体来劫持这一宿主信号通路，IKK是一种可由肿瘤坏死因子诱导的IKB激酶。反过来，TAX将IKK转化为一种结构性活性的激酶，该激酶专门用于蛋白水解性破坏核因子-kB的细胞质抑制物。这是一项继续剖析税收对IKK作用的病理机制的项目的申请。在本供资期间进行的研究表明，这一机制涉及税收诱导的IKK的磷酸化和泛素化。这两个翻译后修饰是生化偶联的。此外，在表达YopJ的细胞中，依赖于税收的泛素(Ub)与IKK的结合被破坏。YopJ是一种Ub样蛋白蛋白酶，可以抑制NF-kB信号转导。正在研究的中心假说是，IKK泛素化在正常和病理生理学的NF-kB信号调节中起着关键作用。为了验证这一中心假设，我们提出了以下实验：(I)IKK中对Tax癌蛋白和促炎激动剂的反应而被修饰的Ub受体位点；(Ii)ikk的生化机制和功能 泛素化在核因子-kB信号转导中的作用，以及(Iii)IKK泛素化在税务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新的涉及IKK泛素化的分子靶点，用于癌症、炎症和自身免疫的治疗干预。本申请的工作范围响应题为“泛素和类似泛素的修饰调节疾病过程”的程序公告PA-03-145。

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".