Abstract
Cyclins are one of the pivotal determinants regulating cell cycle progression. We previously reported that the trans-activator Tax of human T-cell leukemia virus type I (HTLV-I) induces endogenous cyclin D2 expression along with cell cycle progression in a resting human T-cell line, Kit 225, suggesting a role of cyclin D2 in Tax-mediated cell cycle progression. The cyclin D2 gene has a typical E2F binding element, raising the possibility that induction of cyclin D2 expression is a consequence of cell cycle progression. In this study, we examined the role and molecular mechanism of induction of the endogenous human cyclin D2 gene by Tax. Introduction of p19INK4d, a cyclin dependent kinase (CDK) inhibitor of the INK4 family specific for D-type CDK, inhibited Tax-mediated activation of E2F, indicating requirement of D-type CDK in Tax-mediated activation of E2F. Previously indicated E2F binding element and two NF-κB-like binding elements in the 1.6 kbp cyclin D2 promoter fragment had little, if any, effect on responsiveness to Tax. We found that trans-activation of the cyclin D2 promoter by Tax was mainly mediated by a newly identified NF-κB-like element with auxiliary contribution of a CRE-like element residing in sequences downstream of −444 which were by themselves sufficient for trans-activation by Tax. These results indicate that Tax directly trans-activates the cyclin D2 gene, resulting in growth promotion and perhaps leukemogenesis through activation of D-type CDK.
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Acknowledgements
We thank J Hamuro for IL-2. 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, and in part by a grant from The Naito Foundation.
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Huang, Y., Ohtani, K., Iwanaga, R. et al. Direct trans-activation of the human cyclin D2 gene by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene 20, 1094–1102 (2001). https://doi.org/10.1038/sj.onc.1204198
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DOI: https://doi.org/10.1038/sj.onc.1204198
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