Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by tax protein of HTLV-1 through two distinct mechanisms

Tax oncoprotein of human T-cell leukemia virus type 1 (HTLV-1) affects mult iple regulatory processes of infected cells through activation and repressi on of specific transcription and also through modulation of functions of ce ll cycle regulators. Previously, we found that Tax binds to p16ink4a, a mem ber of the INK4 family of cyclin-dependent kinase inhibitors, and counterac ts its inhibitory activity, resulting in cell cycle progression. In this st udy, we examined the effects of Tax on other members of the INK4 family and found that Tax can bind to p15ink4b similarly to p16ink4a, but not to p18i nk4c and p19ink4d. Tax binding to p15ink4b inactivated its function and res tored CDK4 kinase activity. Accordingly, Tax-expressing cells became resist ant to p15ink4b-mediated growth arrest induced by TGF beta. On the other ha nd, expression of p18ink4c was transcriptionally repressed by Tax through t he E-box element of the promoter, which may contribute to the marked reduct ion of p18ink4c mRNA in HTLV-1-infected T-cells. These observations indicat e that Tax suppresses the inhibitory activities of INK4 family members thro ugh two independent mechanisms: functional inhibition of two INK4 proteins and repression of expression of another INK4 protein. These effects may pla y roles in HTLV-1-induced deregulation of the cell cycle, possibly promotin g cellular transformation. (C) 1999 Academic Press.