Abstract

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive clonal malignancy of CD4+ T cells. HTLV-I encodes a regulatory protein, Tax, which is responsible for the transforming potential of HTLV-I. Tax transformation depends upon its ability to activate cellular growth regulatory genes, although the precise mechanism of transformation remains unknown. We have recently demonstrated that Tax can activate expression of the proliferating cell nuclear antigen (PCNA) promoter. PCNA is a required co-factor of DNA polymerase delta, and its expression is intimately linked to cell growth and transformation. PCNA coordinately regulates both DNA replication and repair via a complex series of stoichiometric interactions with cell cycle regulatory proteins. Aberrant PCNA expression is thought to uncouple replication and repair activities such that DNA can be replicated before repair is complete. Thus, activation of PCNA expression by Tax may contribute to cellular proliferation and abnormal repair of damaged DNA, ultimately resulting in oncogenic transformation. The proposed studies will determine the mechanism of Tax transactivation of the human PCNA promoter. In addition, the effects of Tax activated PCNA gene expression on the accumulation of cellular DNA damage and transformation will be investigated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077371-03
Application #
6350276
Study Section
Virology Study Section (VR)
Program Officer
Cole, John S
Project Start
1999-04-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2001
Total Cost
$219,656
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Dayaram, Tajhal; Lemoine, Francene J; Donehower, Lawrence A et al. (2013) Activation of WIP1 phosphatase by HTLV-1 Tax mitigates the cellular response to DNA damage. PLoS One 8:e55989
Ducu, Razvan I; Dayaram, Tajhal; Marriott, Susan J (2011) The HTLV-1 Tax oncoprotein represses Ku80 gene expression. Virology 416:1-8
Guimaraes-Correa, Ana B; Crawford, Lindsey B; Figueiredo, Carlos R et al. (2011) C7a, a biphosphinic cyclopalladated compound, efficiently controls the development of a patient-derived xenograft model of adult T cell leukemia/lymphoma. Viruses 3:1041-58
Dayaram, Tajhal; Marriott, Susan J (2008) Effect of transforming viruses on molecular mechanisms associated with cancer. J Cell Physiol 216:309-14
Edwards, Dustin C; Marriott, Susan J (2008) Human T-cell leukemia virus type 1 Tax relieves repression of proliferating cell nuclear antigen gene expression. J Virol 82:11714-22
Chandhasin, Chandtip; Ducu, Razvan I; Berkovich, Elijahu et al. (2008) Human T-cell leukemia virus type 1 tax attenuates the ATM-mediated cellular DNA damage response. J Virol 82:6952-61
Gatza, Michael L; Dayaram, Tajhal; Marriott, Susan J (2007) Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export. Retrovirology 4:95
Winter, Heather Y; Dayaram, Tajhal; Marriott, Susan J (2007) Activation of the human T-cell leukemia virus type 1 long terminal repeat by the ternary complex factor Elk-1. J Virol 81:13075-81
Winter, Heather Y; Marriott, Susan J (2007) Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J Virol 81:6089-98
Gatza, Michael L; Marriott, Susan J (2006) Genotoxic stress and cellular stress alter the subcellular distribution of human T-cell leukemia virus type 1 tax through a CRM1-dependent mechanism. J Virol 80:6657-68

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