HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 oncoprotein Tax is known to induce DNA damage, micronuclei formation, multinucleation, and DNA aneupoidy. The genomic instability induced by Tax is thought to play an important role in ATLL development. We have shown that the 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 premature poly- ubiquitination and degradation of cell cycle regulators including cyclin A, cyclin B, securin, and Skp2. Skp2 is the substrate-targeting subunit of another E3 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 by Tax and mRNA stabilization due to Tax-induced APC/C activation. The massive surge in p21 and p27 in turn induces rapid senescence (Tax-IRS). Importantly, 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, escaped Tax- IRS and continue to divide after HTLV-1 infection or Tax expression. They however developed dramatic multinucleation and double-stranded DNA breaks, most likely as a result of constitutive APC/C activation. As might be expected, p27 is down-regulated and p21, mis-localized, in HTLV-1-transformed T (HTxT) cells which express Tax abundantly. The p21 and p27 deficiencies apparently allow HTxT cells to overcome Tax-induced senescence. Consistent with the idea that precocious activation of APC/C is deleterious to the cell, we recently found that the prototypic HTxT cell line, MT4, in addition to p21 and p27 deficiencies, expressed a much lower level of Cdh1, the substrate-targeting subunit of APC/C. Recent data from multiple labs indicate that premature APC/C activation through the depletion of Emi1, the S/G2 inhibitor of APC/C, disrupts Cdt1-geminin imbalance and promotes re-replication of DNA. The aberrant DNA replication (re-/hyper-replication) in turn causes multinucleation, double-stranded DNA breaks and DNA damage checkpoint activation. Emi1 depletion also results in premature degradation of Skp2 by APC/C, p27 stabilization, and senescence. Remarkably, the cell cycle phenotypes of Emi1 knockdown resemble those of Tax. These new findings validate our observations and raise many more interesting questions that will be addressed in the following three specific aims:
aim 1, to elucidate the mechanism by which Tax activates APC/C;
aim 2, to investigate the biological consequences of Tax-mediated APC/C activation;
and aim 3, to determine how transformed T cells adapt to Tax expression.

Public Health Relevance

Human T-lymphotropic virus type I (HTLV-1) infects more than 20 million people world-wide. A significant percentage of infected individuals develop adult T-cell leukemia and a paralytic neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis. This project will elucidate the mechanism by which HTLV-1 oncoprotein Tax disrupts cellular control over DNA replication and induces senescence. The study will provide molecular insights that can lead to the development of treatment strategies for human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115884-10
Application #
8616344
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2005-06-23
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
10
Fiscal Year
2014
Total Cost
$250,418
Indirect Cost
$86,746
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Zhi, H; Zahoor, M A; Shudofsky, A M D et al. (2015) KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-?B hyperactivation. Oncogene 34:496-505
Philip, Subha; Zahoor, Muhammad Atif; Zhi, Huijun et al. (2014) Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex. PLoS Pathog 10:e1004040
Zahoor, Muhammad Atif; Philip, Subha; Zhi, Huijun et al. (2014) NF-?B inhibition facilitates the establishment of cell lines that chronically produce human T-lymphotropic virus type 1 viral particles. J Virol 88:3496-504
Balistrieri, Glorilee; Barrios, Christy; Castillo, Laura et al. (2013) Induction of CC-chemokines with antiviral function in macrophages by the human T lymphotropic virus type 2 transactivating protein, Tax2. Viral Immunol 26:3-12
Yang, Liangpeng; Kotomura, Naoe; Ho, Yik-Khuan et al. (2011) Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax. J Virol 85:3001-9
Zhai, Bing; Zhou, Henry; Yang, Liangpeng et al. (2010) Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect. J Antimicrob Chemother 65:931-8
Zhang, Ling; Zhi, Huijun; Liu, Meihong et al. (2009) Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization. Retrovirology 6:35
Liu, Meihong; Yang, Liangpeng; Zhang, Ling et al. (2008) Human T-cell leukemia virus type 1 infection leads to arrest in the G1 phase of the cell cycle. J Virol 82:8442-55
Giam, Chou-Zen; Jeang, Kuan-Teh (2007) HTLV-1 Tax and adult T-cell leukemia. Front Biosci 12:1496-507
Soung, Nak-Kyun; Kang, Young Hwi; Kim, Keetae et al. (2006) Requirement of hCenexin for proper mitotic functions of polo-like kinase 1 at the centrosomes. Mol Cell Biol 26:8316-35

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