Activation of the cyclin D2 and cdk6 genes through NF-kappaB is critical for cell-cycle progression induced by HTLV-I Tax.
Human T-cell leukemia virus type I (HTLV-I) can infect a variety of cell types, so the cause of T-cell-specific oncogenesis remains to be elucidated. The trans-activator protein Tax of HTLV-I can promote cell-cycle progression in resting T cells along with induction of cyclin D2 and cyclin-dependent kinase (cdk6) gene expression. Here, we found that Tax cannot induce cell-cycle progression in resting fibroblasts and analysed the molecular basis of the cell-type specificity. Tax activated cyclin D2 and cdk6 promoters in T cells, but not in fibroblasts, depending on its ability to activate the transcription factor nuclear factor (NF)-kappaB. Expression of cyclin D2 and CDK6 activated the transcription factor E2F, which is essential for cell-cycle progression, in both T cells and fibroblasts. Short-hairpin RNA (shRNA)-mediated inhibition of cyclin D2 and CDK6 induction suppressed Tax-induced activation of E2F in T cells. Finally, shRNA-mediated downregulation of NF-kappaB p65 or p100 expression reduced Tax-induced activation of cyclin D2 and/or cdk6 promoters and cell-cycle progression in T cells. These results indicate that Tax-induced cell-cycle progression in T cells is mediated, at least in part, through cell-type-specific activation of the cyclin D2 and cdk6 genes through NF-kappaB and may be important for the cell-type-specific oncogenesis.
Iwanaga
R
R
Laboratory of Microbiology and Immunology, Graduate School of Health Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Ozono
E
E
Fujisawa
J
J
Ikeda
M A
MA
Okamura
N
N
Huang
Y
Y
Ohtani
K
K
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D056742:Cyclin D2 / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D050684:E2F Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats
D056742:Cyclin D2; D050684:E2F Transcription Factors; D016356:Gene Products, tax; D016328:NF-kappa B; C514970:tax protein, Human T-lymphotrophic virus 1; D051361:Cyclin-Dependent Kinase 6