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Journal of Virology, November 1998, p. 8852-8860, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Human T-Cell Lymphotropic/Leukemia Virus Type 1 Tax Abrogates p53-Induced Cell Cycle Arrest and Apoptosis through Its CREB/ATF Functional Domain

J. C. Mulloy,1,* T. Kislyakova,1,dagger A. Cereseto,1 L. Casareto,1 A. LoMonico,1 J. Fullen,1 M. V. Lorenzi,2 A. Cara,1,Dagger C. Nicot,1 C.-Z. Giam,3 and G. Franchini1

Basic Research Laboratory1 and Laboratory of Cellular and Molecular Biology,2 Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, and Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 208143

Received 21 April 1998/Accepted 4 August 1998

Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) transforms human T cells in vitro, and Tax, a potent transactivator of viral and cellular genes, plays a key role in cell immortalization. Tax activity is mediated by interaction with cellular transcription factors including members of the CREB/ATF family, the NF-kappa B/c-Rel family, serum response factor, and the coactivators CREB binding protein-p300. Although p53 is usually not mutated in HTLV-1-infected T cells, its half-life is increased and its function is impaired. Here we report that transient coexpression of p53 and Tax results in the suppression of p53 transcriptional activity. Expression of Tax abrogates p53-induced G1 arrest in the Calu-6 cell line and prevents the apoptosis induced by overexpressing p53 in the HeLa/Tat cell line. The Tax mutants M22 and G148V, which selectively activate the CREB/ATF pathway, exert these same biological effects on p53 function. In contrast, the NF-kappa B-active Tax mutant M47 has no effect on p53 activity in any of these systems. Consistent with the negative effect of Tax on p53, no activity on a p53-responsive promoter was observed upon transfection of HTLV-1-infected T-cell lines. The p53 protein is expressed at high levels in the nucleus, and nuclear extracts of HTLV-1-infected T cells bind constitutively to a DNA oligonucleotide containing the p53 response element, indicating that Tax does not interfere with p53 binding to DNA. Tax is able to suppress the transactivation function of p53 in three different cell lines, and this suppression required Tax-mediated activation of the CREB/ATF, but not the NF-kappa B/c-Rel, pathway. Tax and the active Tax mutants were able to abrogate the G1 arrest and apoptosis induced by p53, and this effect does not correlate with an altered localization of nuclear p53 or with the disruption of p53-DNA complexes. The suppression of p53 activity by Tax could be important in T-cell immortalization induced by HTLV-1.

* Corresponding author. Mailing address: Basic Research Laboratory, National Cancer Institute, 37 Convent Dr., Bldg. 37, Room 6A11, Bethesda, MD 20892. Phone: (301) 496-2386. Fax: (301) 496-8394. E-mail: jmulloy{at}helix.nih.gov.

dagger Present address: Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.

Dagger Present address: Mt. Sinai Medical Center, Division of Infectious Disease, New York, NY 10029.

Journal of Virology, November 1998, p. 8852-8860, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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