Cell Cycle Regulation and Adult T Cell Leukemia

细胞周期调节和成人 T 细胞白血病

• 批准号: 8448784
• 负责人: CHOU-ZEN GIAM
• 金额: $ 28.95万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448784
• 关键词: Address; Adult; Affect; Anaphase; Aneuploidy; Biological; CD4 Positive T Lymphocytes; CDK2 gene; CDKN1A gene; Cell Aging; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cells; Chromosomal Instability; Cyclin A; Cyclin B; Cyclin E; DNA; DNA Damage; DNA biosynthesis; Development; Down-Regulation; Etiology; G2 Phase; Hela Cells; Human; Human T-lymphotropic virus 1; Individual; Infection; Lead; Licensing Factor; Malignant Neoplasms; Mediating; Messenger RNA; Metaphase; Mitotic; Molecular; Nuclear; Oncogene Proteins; Paralysed; Pathway interactions; Phosphorylation; Proteins; Ras/Raf; Replication Licensing; Role; Signal Pathway; Spinal Cord Diseases; T-Cell Leukemia; T-Cell Transformation; T-Lymphocyte; Taxes; Testing; Time; Trans-Activators; Tropical Spastic Paraparesis; Ubiquitination; Up-Regulation; Viral; Virus; anaphase-promoting complex; cell transformation; human PTTG1 protein; inhibitor/antagonist; insight; leukemia; leukemia/lymphoma; nervous system disorder; osteosarcoma; premature; prevent; promoter; public health relevance; senescence; treatment strategy; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL), a malignancy of CD4+ T cells whose etiology is associated with the viral transactivator/oncoprotein, Tax. We have shown that Tax can activate the anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls metaphase to anaphase transition and mitotic exit. APC/C activation by Tax leads to the premature poly-ubiquitination and degradation of mitotic regulators including cyclin A, cyclin B, securin, and Skp2. Skp2 is the substrate-targeting subunit of another E3 ubiquitin ligase known as SCFSkp2, which mediates the destruction of cyclin E/A-CDK2 inhibitor (CKI), p27. The degradation of Skp2 by APC/C as induced by Tax leads to SCFSkp2 inactivation and p27 stabilization. The mRNA level of another CKI, p21, also increases sharply as a result of promoter activation and mRNA stabilization by Tax. The great surge in p21 and p27 in turn induces cellular senescence termed Tax-induced rapid senescence (Tax-IRS). As expected, HeLa and SupT1 T cells infected by HTLV-1 arrest in senescence as well. By contrast, cells deficient in p21 and p27, such as HOS, escape Tax-IRS and continue to divide after HTLV-1 infection or Tax expression. They, however, develop dramatic nuclear abnormalities in the form of multinucleation and DNA aneuploidy. Importantly, down-regulation of p27 and mis-localization of p21 are common in Tax-expressing HTLV-1-transformed T (HTxT) cells and most likely occur through activation of the PI3K- Akt pathway. Our latest results showed that Tax caused significant accumulation of the DNA replication licensing factor, Cdt1, during S/G2. In a most exciting recent development, we found that inhibition of NF-?B activation by Tax completely abrogated Tax-IRS. Our findings raise several important questions: How does persistent NF-?B activation lead to p21/p27 upregulation and senescence? Does NF-?B activation lie upstream of APC/C activation and Cdt1 accumulation? Does the accumulation of Cdt1 induced by Tax lead to DNA re/hyper-replication and can it explain the dramatic nuclear abnormalities seen in Tax-expressing cells? Finally, the senescence-like arrest induced by HTLV-1 in SupT1 and HeLa cells suggests that primary T cells productively infected by HTLV-1 likely also undergo senescence. If so, then how does a virus that induces senescence cause leukemia? How do HTxT cell lines manage to adapt to Tax and continue to divide? To address these questions and to elucidate the pathway by which HTLV-1 infection leads to T cell transformation and ATL, three specific aims are proposed: (1) to delineate the pathway leading from persistent NF-?B activation by Tax to senescence; (2) to investigate the cause and biological effects of HTLV- and Tax-induced chromosome instability; and (3) to elucidate the mechanisms by which cells become adapted to (transformed by) Tax and HTLV-1.

描述（由申请人提供）：HTLV-I是成人T细胞白血病/淋巴瘤（ATL）的病原体，ATL是CD4+T细胞的恶性肿瘤，其病因与病毒反式激活因子/癌蛋白Tax有关。我们已经证明，Tax 可以激活后期促进复合物/环体 (APC/C)，这是一种控制中期到后期转变和有丝分裂退出的 E3 泛素连接酶。 Tax 激活 APC/C 会导致有丝分裂调节因子过早多泛素化和降解，包括细胞周期蛋白 A、细胞周期蛋白 B、securin 和 Skp2。 Skp2 是另一种 E3 泛素连接酶 SCFSkp2 的底物靶向亚基，它介导细胞周期蛋白 E/A-CDK2 抑制剂 (CKI) p27 的破坏。 Tax 诱导的 APC/C 对 Skp2 的降解导致 SCFSkp2 失活和 p27 稳定。由于启动子激活和 Tax 稳定 mRNA，另一种 CKI p21 的 mRNA 水平也急剧增加。 p21 和 p27 的大幅增加反过来会诱导细胞衰老，称为 Tax 诱导的快速衰老 (Tax-IRS)。正如预期的那样，被 HTLV-1 感染的 HeLa 和 SupT1 T 细胞也出现衰老停滞。相比之下，缺乏 p21 和 p27 的细胞（例如 HOS）会逃避 Tax-IRS，并在 HTLV-1 感染或 Tax 表达后继续分裂。然而，它们会出现多核和 DNA 非整倍体形式的严重核异常。重要的是，p27 的下调和 p21 的错误定位在表达 Tax 的 HTLV-1 转化 T (HTxT) 细胞中很常见，并且很可能通过激活 PI3K-Akt 通路而发生。我们的最新结果表明，Tax 在 S/G2 期间导致 DNA 复制许可因子 Cdt1 显着积累。最近最令人兴奋的进展是，我们发现通过 Tax 抑制 NF-κB 激活可以完全废除 Tax-IRS。我们的研究结果提出了几个重要问题：持续的 NF-κB 激活如何导致 p21/p27 上调和衰老？ NF-κB 激活是否位于 APC/C 激活和 Cdt1 积累的上游？ Tax 诱导的 Cdt1 积累是否会导致 DNA 重新/过度复制？它能否解释 Tax 表达细胞中出现的剧烈核异常？最后，HTLV-1 在 SupT1 和 HeLa 细胞中诱导的衰老样停滞表明，被 HTLV-1 有效感染的原代 T 细胞也可能经历衰老。如果是这样，那么诱导衰老的病毒是如何导致白血病的呢？ HTxT 细胞系如何适应 Tax 并继续分裂？为了解决这些问题并阐明HTLV-1感染导致T细胞转化和ATL的途径，提出了三个具体目标：（1）描绘从Tax持续激活NF-κB到衰老的途径； (2) 研究HTLV和Tax诱导的染色体不稳定性的原因和生物学效应； (3) 阐明细胞适应 Tax 和 HTLV-1（转化）的机制。