title: Human T-cell leukemia virus type 1 Tax activates cyclin-dependent kinase inhibitor p21/Waf1/Cip1 expression through a p53-independent mechanism: Inhibition of cdk2.
abstract: We investigated the possible involvement of HTLV-1 Tax in the transcriptional activation of p21/Waf1/Cip1 (hereafter p21), a potent inhibitor of cyclin-dependent kinases and cell growth. Tax transfection resulted in enhanced expression of p21 protein in T and fibroblastoid cells. Similarly, Tax-expressing cells have higher amounts of endogenous p21 protein and RNA. However, neither Tax-negative, HTLV-1 transformed cells or HTLV-1-negative T cell lines had detectable levels of p21 protein and RNA. Cotransfection of Tax strongly activated the p21 promoter. CREB/ATF defective Tax mutant (M47) activated the p21 promoter significantly less efficiently. Tax activated wild type (wt) p21 promoter in p53-negative Jurkat and p53-positive A301cells, irrespective of endogenous p53 status, and activated a mutant p21 promoter containing a p53 responsive element (p53RE) deletion as strongly as wt promoter. Of importance, cdk2 activity was almost completely abolished in Tax-induced p21-expressing MT-2 cells, suggesting that Tax-induced p21 predominantly affects the activity of cdk2, a late G1 and S phase kinase. Taken together, these findings suggest that HTLV-1 Tax activates p21/Waf1/Cip1, a cell growth inhibitor, in a p53-independent mechanism through CREB/ATF-related transcription factors, and inhibits cdk2. Tax induction of p21 may balance the T-cell proliferation function of Tax and may contribute to the long clinical latency of HTLV-1 infection and the delayed development of adult T-cell leukemia.
authors.affiliation: Department of Vaccine Development and Research, Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD, USA. chowdhui@mail.nih.gov
authors.forename: Iqbal H
authors.initials: IH
authors.lastname: Chowdhury
authors.forename: Arash
authors.initials: A
authors.lastname: Farhadi
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Birx
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D051696:Activating Transcription Factors; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051696:Activating Transcription Factors; D001798:Blood Proteins; C493956:CDKN1A protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016356:Gene Products, tax; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2