Abstract
The trans-activator protein Tax of human T-cell leukemia virus type I (HTLV-I) plays an important role in the development of adult T-cell leukemia through, at least in part, its ability to stimulate cell growth. We previously reported that Tax induced cell cycle progression from G0/G1 phase to S and G2/M phases in human T-cell line Kit 225 cells. To elucidate molecular mechanism of Tax-induced cell cycle progression, we systematically examined the effects of Tax on biochemical events associated with cell cycle progression. Introduction of Tax into resting Kit 225 cells induced activation of the G1/S transition regulation cascade consisting of activation of cyclin dependent kinase 2 (CDK2) and CDK4, phosphorylation of the Rb family proteins and an increase in free E2F. The kinase activation was found to result from Tax-induced expression of genes for cell cycle regulatory molecules including cyclin D2, cyclin E, E2F1, CDK2, CDK4 and CDK6, and Tax-induced reduction of CDK inhibitors p19INK4d and p27Kip1. These modulations by Tax always paralleled the ability of Tax to activate the NF-κB transcription pathway. These results indicate the important role of Tax-mediated trans-activation of the genes for cell cycle regulatory molecules in Tax-induced cell cycle progression.
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Acknowledgements
We thank J Hamuro for IL-2, B Amati and G Peters for plasmids and M Yoshida for recombinant adenoviruses. This work was supported in part by a Grant-in-Aid for General Scientific Research and Cancer Research from the Ministry of Education, Science, Sports and Culture, in part by a grant from CREST (Core Research for Evolutional Science and Technology) of the Japan Science and Technology Corporation (JST), in part by a grant from NOVARTIS Foundation (Japan) for the Promotion of Science, in part by a grant from Osaka Cancer Foundation, and in part by a grant from The Naito Foundation.
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Iwanaga, R., Ohtani, K., Hayashi, T. et al. Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 20, 2055–2067 (2001). https://doi.org/10.1038/sj.onc.1204304
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DOI: https://doi.org/10.1038/sj.onc.1204304
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