Abstract
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)-κB. 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-κB 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-κB and may be important for the cell-type-specific oncogenesis.
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Acknowledgements
We thank S Yamaoka for critical comments on western blot analysis of p100. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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Iwanaga, R., Ozono, E., Fujisawa, J. et al. Activation of the cyclin D2 and cdk6 genes through NF-κB is critical for cell-cycle progression induced by HTLV-I Tax. Oncogene 27, 5635–5642 (2008). https://doi.org/10.1038/onc.2008.174
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DOI: https://doi.org/10.1038/onc.2008.174
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