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J Virol, February 1998, p. 1165-1170, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inhibition of p53 Transactivation Function by the Human T-Cell Lymphotropic Virus Type 1 Tax Protein

Cynthia A. Pise-Masison,1 Kyeong-Sook Choi,1,dagger Michael Radonovich,1 Jürgen Dittmer,1,Dagger Seong-Jin Kim,2 and John N. Brady1,*

Laboratory of Receptor Biology and Gene Expression1 and Laboratory of Chemoprevention,2 Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892

Received 10 June 1997/Accepted 22 October 1997

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia. HTLV-1 transforms lymphocytes, and there is increasing evidence that the virus-encoded protein, Tax, plays a primary role in viral transformation. We have shown that wild-type p53 in HTLV-1-transformed cells is stabilized. This study was initiated to directly analyze whether the p53 in HTLV-1-transformed cell lines was transcriptionally active and to identify the viral gene product responsible for stabilization and inactivation. Transfection experiments using a p53-responsive reporter plasmid and gamma -irradiation studies demonstrate that the wild-type p53 in HTLV-1-transformed cell lines is not fully active. Further, we demonstrate that the HTLV-1-transforming protein, Tax, stabilizes and inactivates p53 function. Cotransfection of Tax with p53 results in a greater than 10-fold reduction in p53 transcription activity. Using Gal4-p53 fusion proteins, we demonstrate that Tax inhibition of p53 transactivation function is independent of sequence-specific DNA binding. Moreover, Tax inhibits p53 function by interfering with the activity of the N-terminal activation domain (amino acids 1 to 52). We conclude that Tax is involved in the inactivation of p53 function and stabilization of p53 in HTLV-1-infected cells. The functional interference of p53 function by Tax may be important for transformation and leukemogenesis.

* Corresponding author. Mailing address: Laboratory of Receptor Biology and Gene Expression, Division of Basic Sciences, National Cancer Institute, 41 Library Dr., 41/B403, Bethesda, MD 20892. Phone: (301) 496-0986. Fax: (301) 496-4951. E-mail: bradyj{at}dce41.nci.nih.gov.

dagger Present address: Department of Biochemistry, Ajou University of Medicine, Su Won 442-749, Korea.

Dagger Present address: Institut für Zellbiologie, Abteilung Molekularbiologie, Eberhard-Karls-Universitat Tübingen, 72076 Tübingen, Germany.




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