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Gadd45a contributes to p53 stabilization in response to DNA damage

Oncogene volume 22, pages 8536–8540 (2003)Cite this article

Abstract

p53 is an important molecule in cellular response to DNA damage. After genotoxic stress, p53 protein stabilizes transiently and accumulates in the nucleus, where it functions as a transcription factor and upregulates multiple downstream-targeted genes, including p21Waf1/Cip1, Gadd45a and Bax. However, regulation of p53 stabilization is complex and may mainly involve post-translational modification of p53, such as phosphorylation and acetylation. Using mouse embryonic fibroblasts (MEFs) derived from Gadd45a knockouts, we found that disruption of Gadd45a greatly abolished p53 protein stabilization following UVB treatment. Phosphorylation of p53 at Ser-15 was substantially reduced in Gadd45a−/− MEFs. In addition, p53 induction by UVB was shown to be greatly abrogated in the presence of p38 kinase inhibitor, but not c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK), suggesting that p38 protein kinase is involved in the regulation of p53 induction. Along with the findings presented above, inducible expression of Gadd45a enhanced p53 accumulation after cell exposure to UVB. Taken together, the current study demonstrates that Gadd45a, a conventional downstream gene of p53, may play a role as an upstream effector in p53 stabilization following DNA damage, and thus has defined a positive feedback signal in the activation of the p53 pathway.

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Acknowledgements

We are grateful to Albert J Fornace and M Christine Hollander for providing us with ER1 and ER-11 cell lines, as well as constructive discussion during the project. This work is supported in part by National Institutes of Health Grant R01 CA-83874, DOD Grant DAMD17-00-1-0414, National Key Basic Research Program (2002 CB513101) and National Natural Science Foundation of China Grant (30225018).

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Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, 100021, China

    Shunqian Jin, Tong Tong, Yongmei Song, Shao Shujuan, Min Wu & Qimin Zhan

  2. Department of Radiation Oncology, Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA

    Shunqian Jin, Lucia Mazzacurati, Xiaocheng Zhu, Kimberly L Petrik & Qimin Zhan

  3. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA

    Baskaran Rajasekaran & Qimin Zhan

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  1. Shunqian Jin
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Correspondence to Qimin Zhan.

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Jin, S., Mazzacurati, L., Zhu, X. et al. Gadd45a contributes to p53 stabilization in response to DNA damage. Oncogene 22, 8536–8540 (2003). https://doi.org/10.1038/sj.onc.1206907

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