P53 FUNCTIONAL IMPAIRMENT AND HIGH P21(WAF1 CIP1) EXPRESSION IN HUMANT-CELL LYMPHOTROPIC/LEUKEMIA VIRUS TYPE I-TRANSFORMED T-CELLS/

Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some o f the mechanisms responsible for transformation remain unknown, increa sing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential rol e of the tumor suppressor gene p53 and of the p53-regulated gene, p21( waf1/cip1) (wild-type p53 activated fragment 1/ cycling dependent kina ses [cdks] interacting protein 1), in HTLV-l-infected T cells. We have found that the majority of HTLV-l-infected T cells have the wild-type p53 gene. However, its function in HTLV-l-transformed cells appears t o be impaired, as shown by the lack of appropriate p53-mediated respon ses to ionizing radiation (IR). Interestingly, the expression of the p 53 inducible gene, p21(waf1/cip1), is elevated at the messenger ribonu cleic acid and protein levels in all HTLV-I-infected T-cell lines exam ined as well as in Taxi-1, a human T-cell line stably expressing Tax, Additionally, Tax induces upregulation of a p21(waf1/cip1) promoter-dr iven luciferase gene in p53 null cells, and increases p21(waf1/cip1) e xpression in Jurkat T cells. These findings suggest that the Tax prote in is at least partially responsible for the p53-independent expressio n of p21(waf1/cip1) in HTLV-l-infected cells. Dysregulation of p53 and p21(waf1/cip1) proteins regulating cell-cycle progression, may repres ent an important step in HTLV-l-induced T-cell transformation. (C) 199 6 by The American Society of Hematology.