p53 Functional impairment and high p21(waf1/cip1) expression in human T- cell lymphotropic/leukemia virus type I - Transformed T cells

Abstract

Human T-cell lymphotropic/leukemia virus type I (HTLV-I) is associated with T-cell transformation both in vivo and in vitro. Although some of the mechanisms responsible for transformation remain unknown, increasing evidence supports a direct role of viral as well as dysregulated cellular proteins in transformation. We investigated the potential role of the tumor suppressor gene p53 and of the p53-regulated gene, p21(waf1/cip1) (wild-type p53 activated fragment 1/cycling dependent kinases [cdks] interacting protein 1), in HTLV-I-infected T cells. We have found that the majority of HTLV-I- infected T cells have the wild-type p53 gene. However, its function in HTL V- I-transformed cells appears to be impaired, as shown by the lack of appropriate p53-mediated responses to ionizing radiation (IR). Interestingly, the expression of the p53 inducible gene, p21(waf1/cip1), is elevated at the messenger ribonucleic acid and protein levels in all HTLV-I-infected T-cell lines examined as well as in Taxl-1, a human T-cell line stably expressing Tax. Additionally, Tax induces upregulation of a p21(waf1/cip1) promoter- driven luciferase gene in p53 null cells, and increases p21(waf1/cip1) expression in Jurkat T cells. These findings suggest that the Tax protein is at least partially responsible for the p53-independent expression of p21(waf1/cip1) in HTLV-I-infected cells. Dysregulation of p53 and p21(waf1/cip1) proteins regulating cell-cycle progression, may represent an important step in HTLV-I-induced T-cell transformation.