HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4.
Tax, a regulatory protein of human T-cell leukemia virus type 1 (HTLV-1), is an oncoprotein which immortalizes human T cells and induces tumors in transgenic mice. These effects may be due to its interaction with cellular proteins, consisting of several transcription factors including CREB, NF-kappa B and SRF, and the transcriptional inhibitor, I kappa B. Here, we found that Tax binds to a cyclin-dependent kinase inhibitor, p16INK4A, which has ankyrin motifs similar to I kappa B. p16INK4A binds to the 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 in the p16INK4A-CDK4 complex, with subsequent activation of CDK4 kinase. Tax also suppressed p16INK4A-mediated inhibition of U2OS 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 induced by HTLV-1 infection.
Suzuki
T
T
Department of Cellular and Molecular Biology, University of Tokyo, Japan.
Kitao
S
S
Matsushime
H
H
Yoshida
M
M
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D002472:Cell Transformation, Viral; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D004791:Enzyme Inhibitors; D016356:Gene Products, tax; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases