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Journal of Virology, August 2000, p. 7270-7283, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Overexpression of p21waf1 in Human T-Cell Lymphotropic Virus Type 1-Infected Cells and Its Association with Cyclin A/cdk2

Cynthia de la Fuente,1 Francisco Santiago,1 Siew Yen Chong,1 Longwen Deng,1 Todd Mayhood,1 Peng Fu,1 Dana Stein,2 Thomas Denny,2 Frederick Coffman,3 Nazli Azimi,4 Renaud Mahieux,5 and Fatah Kashanchi1,*

Department of Biochemistry and Molecular Biology,1 Department of Pediatrics,2 and Department of Pathology,3 University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103; National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208744; and Unite d'Oncologie Virale, Department SIDA-Retrovirus, Institut Pasteur, 75724 Paris, France5

Received 30 November 1999/Accepted 19 May 2000

Human T-cell lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). T-cell transformation is mainly due to the actions of the viral phosphoprotein Tax. Tax interacts with multiple transcriptional factors, aiding the transcription of many cellular genes. Here, we report that the cyclin-dependent kinase inhibitor p21/waf1 is overexpressed in all HTLV-1-infected cell lines tested as well as in ATL and HAM/TSP patient samples. Tax was found to be able to transactivate the endogenous p21/waf1 promoter, as detected by RNase protection, as well as activate a series of wild-type and 5'-deletion constructs linked to a luciferase reporter cassette. Wild-type but not a mutant form of Tax (M47) transactivated the p21/waf1 promoter in a p53-independent manner and utilized a minimal promoter that contained E2A and TATA box sequences. The p21/waf1 protein was reproducibly observed to be complexed with cyclin A/cdk2 and not with any other known G1, S, or G2/M cyclins. Functionally, the association of p21/cyclin A/cdk2 decreased histone H1 phosphorylation in vitro, as observed in immunoprecipitations followed by kinase assays, and affected other substrates, such as the C terminus of Rb protein involved in c-Abl and histone deacetylase-1 (HDAC1) regulation. Interestingly, upon the use of a stress signal, such as gamma-irradiation, we found that the p21/cyclin A/cdk2 complex was able to block all known phosphorylation sites on the Rb molecule. Finally, using elutriated cell cycle fractions and a stress signal, we observed that the HTLV-1-infected T cells containing wild-type Tax, which had been in early or mid-G1 phase prior to gamma-irradiation, arrested in G1 and did not undergo apoptosis. This may be an important mechanism for an oncogenic virus such as HTLV-1 to stop the host at the G1/S boundary and to repair the damaged DNA upon injury, prior to S-phase entry.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, MSB E635, UMDNJ-New Jersey Medical School, Newark, NJ 07103. Phone: (973) 972-1089. Fax: (973) 972-5594. E-mail: Kashanfa{at}umdnj.edu.

Journal of Virology, August 2000, p. 7270-7283, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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