HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16Ink4a and counteracts its inhibitory activity to CDK4.
Tax, a regulatory protein of HTLV-1, is an oncoprotein which immortalizes human T-cells and induces tumors in transgenic mice. Here, we found that Tax binds to a cyclin-dependent kinase inhibitor, p16Ink4a. p16Ink4a binds to cyclin-dependent kinases, CDK4 and CDK6, and inhibits their activity, resulting in suppression of G1 phase progression. The binding of Tax to p16Ink4a induced a reduction of p16Ink4a/CDK4 complex, with subsequent activation of CDK4 kinase. Tax also suppressed p16Ink4a-mediated inhibition of cell growth. The p16Ink4a gene was frequently deleted in many T-cell lines, but not in HTLV-1-infected T-cell lines. Taking these findings together, the functional inactivation of p16Ink4a by Tax through protein-protein interaction is suggested to contribute to cellular immortalization and transformation by HTLV-1.
Suzuki
T
T
Dept. of Cell. Mol. Biol., Univ. of Tokyo, Japan.
Yoshida
M
M
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D016356:Gene Products, tax / Q000096:biosynthesis / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013601:T-Lymphocytes; D014162:Transfection
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases