INHIBITION OF P53 TRANSACTIVATION FUNCTION BY THE HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-1 TAX PROTEIN

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia. HTLV-1 transforms lymphocytes, and there i s increasing evidence that the virus-encoded protein, Tax, plays a pri mary role in viral transformation, We have shown that wild-type p53 in HTLV-1-transformed cells is stabilized. This study,vas initiated to d irectly analyze whether the p53 in HTLV-1-transformed cell lines,vas t ranscriptionally active and to identify the viral gene product respons ible for stabilization and inactivation. Transfection experiments usin g a p53-responsive reporter plasmid and gamma-irradiation studies demo nstrate that the wild-type p53 in HTLV-1-transformed cell lines is not fully active. Further, we demonstrate that the HTLV-1-transforming pr otein, Tax, stabilizes and inactivates p53 function. Cotransfection of Tax with p53 results in a greater than 10-fold reduction in p53 trans cription activity. Using Gal4-p53 fusion proteins, we demonstrate that Tax inhibition of p53 transactivation function is independent of sequ ence-specific DNA binding. Moreover, Tax inhibits p53 function by inte rfering with the activity of the N-terminal activation domain (amino a cids 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 f unctional interference of p53 function by Tax may be important for tra nsformation and leukemogenesis.