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p12CDK2-AP1 mediates DNA damage responses induced by cisplatin

Oncogene volume 24, pages 407–418 (2005)Cite this article

Abstract

We examined the biological role of p12CDK2-AP1 in cisplatin-mediated responses by using murine ES p12CDK2-AP1 knockout clones generated by a targeted disruption of murine p12CDK2-AP1. Homozygous knockout clones showed an increased cellular proliferation along with an increase in S and a decrease in G2/M phase populations. Interestingly, ES p12CDK2-AP1 knockout clones showed a resistance to cisplatin treatment along with an increased DNA repair activity assessed by host cell reactivation assay using a cisplatin-damaged reporter DNA and a significant reduction of apoptosis upon cisplatin treatment. By using stable p12CDK2-AP1 short interfering RNA (siRNA) clones from human normal oral keratinocytes, we confirmed that downregulation of p12CDK2-AP1 resulted in a resistance to cisplatin. More interestingly, cisplatin treatment resulted in a reduction of CDK2 kinase activity in control clones, but p12CDK2-AP1 knockout clones showed a sustained CDK2 kinase activity. These data suggest that p12CDK2-AP1 plays a role in cisplatin-mediated cellular responses by modulating CDK2 activity. These data further suggest p12CDK2-AP1 is a potential gene therapeutic agent for oral/head and neck cancer in conjunction with DNA-damaging agents such as cisplatin.

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Acknowledgements

We thank Dr Marxa Figueiredo for critical reading of this manuscript and Dr Rick Mortensen for providing us with the vector for generating murine ES targeting construct. This work was supported by PHS Grant T32 DE 007296-08 to YK and RO1 DE 14857 to DTW.

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  1. School of Dentistry and Dental Research Institute, University of California-Los Angeles, Los Angeles, CA, 90095, USA

    Yong Kim, Jim McBride, Rong Zhang, Xiaofeng Zhou & David T Wong

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Correspondence to David T Wong.

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Kim, Y., McBride, J., Zhang, R. et al. p12CDK2-AP1 mediates DNA damage responses induced by cisplatin. Oncogene 24, 407–418 (2005). https://doi.org/10.1038/sj.onc.1208222

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