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Journal of Virology, December 1999, p. 9917-9927, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Transcriptional Up-Regulation of the Cyclin D2 Gene and Acquisition of New Cyclin-Dependent Kinase Partners in Human T-Cell Leukemia Virus Type 1-Infected Cells

Francisco Santiago,1 Elizabeth Clark,1 Siewyen Chong,1 Carlos Molina,1 Fariba Mozafari,2 Renaud Mahieux,3 Masahiro Fujii,4 Nazli Azimi,3 and Fatah Kashanchi1,*

Department Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 071031; Department of Hepatitis and Retroviruses, Pasteur Institute, Tehran, Iran2; National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208743; and Department of Virology, Niigata University School of Medicine, Asahimachi-Dori, Niigata, Japan 951-85104

Received 15 June 1999/Accepted 27 August 1999

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax1 is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax1, provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G1 cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin-dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T-cell leukemia.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, UMDNJ---New Jersey Medical School, MSB E-635, Newark, NJ 07103. Phone: (973) 972-1089. Fax: (973) 972-1172. E-mail: kashanfa{at}njmsa.umdnj.edu.

Journal of Virology, December 1999, p. 9917-9927, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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