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.

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 infection affects the progression of cell division cycle and how these changes impact on the development of leukemia. 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 #
5R01CA140963-05
Application #
8607461
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$277,156
Indirect Cost
$96,008
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
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
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
Zhi, Huijun; Yang, Liangpeng; Kuo, Yu-Liang et al. (2011) NF-*B hyper-activation by HTLV-1 tax induces cellular senescence, but can be alleviated by the viral anti-sense protein HBZ. PLoS Pathog 7:e1002025