Cell Cycle Regulation and Adult T Cell Leukemia

细胞周期调节和成人 T 细胞白血病

基本信息

批准号：
8791965
负责人：
CHOU-ZEN GIAM
金额：
$ 1.98万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791965
关键词：
Address Adult T-Cell Leukemia/Lymphoma 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 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 nervous system disorder osteosarcoma premature prevent promoter public health relevance senescence treatment strategy ubiquitin-protein ligase

项目摘要

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-κB activation by Tax completely abrogated Tax-IRS. Our findings raise several important questions: How does persistent NF-κB activation lead to p21/p27 upregulation and senescence? Does NF-κB 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-κB 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（通过施用）：HTLV-I是成人T细胞白血病/淋巴瘤（ATL）的病因，CD4+的恶性肿瘤告诉LOGY与病毒式转播/癌蛋白有关，我们表明我们表明税收税。后期升高/循环体（APC/C），一种E3泛素连接酶，通过税收控制对后期的跨液和有丝分裂的T. APC/C激活，导致植物前多聚泛素化和包括细胞周期B，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，cyclin a，scheclin a，seculin a，seculin a，seculin a，seculin a，seculin a，seculin a，seculin a，seculin ，SKP2。 P21和P27的大量激增又诱导了税收诱导的快速衰老（税收IR）。逃避税收，并在HTLV-1感染或税收表达后继续划分。表达HTLV-1转化的T（HTXT）细胞，最喜欢税收的税收在S/G2期间导致DNA复制许可因子CDT1的显着累积。废除的税收激活导致p21/p27上调和衰老？在表达税收的细胞中，HTLV-1在Supt1中诱导的scemence样细胞和HELA细胞中的sce液样，这表明HTLV-1的主要T细胞可能会出现衰老，这是HTLV-1的产物。线路能够适应税收并继续分裂？研究HTLV和税收诱导的染色体不稳定性的原因和生物学；