GADD45β mediates p53 protein degradation via Src/PP2A/MDM2 pathway upon arsenite treatment

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Abstract

Growth arrest and DNA-damage-inducible, beta (GADD45b) has been reported to inhibit apoptosis via attenuating c-Jun N-terminal kinase (JNK) activation. We demonstrated here that GADD45b mediated its anti-apoptotic effect via promoting p53 protein degradation following arsenite treatment. We found that p53 protein expression was upregulated in GADD45β-/- cells upon arsenite exposure as compared with those in GADD45β+/+ cells. Further studies showed that GADD45b attenuated p53 protein expression through Src/protein phosphatase 2A/murine double minute 2-dependent p53 protein-degradation pathway. Moreover, we identified that GADD45β-mediated p53 protein degradation was crucial for its anti-apoptotic effect due to arsenite exposure, whereas increased JNK activation was not involved in the increased cell apoptotic response in GADD45β-/- cells under same experimental conditions. Collectively, our results demonstrate a novel molecular mechanism responsible for GADD45β protection of arsenite-exposed cells from cell death, which provides insight into our understanding of GADD45β function and a unique compound arsenite as both a cancer therapeutic reagent and an environmental carcinogen. Those novel findings may also enable us to design more effective strategies for utilization of arsenite for the treatment of cancers. © 2013 Macmillan Publishers Limited. All rights reserved.

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Yu, Y., Huang, H., Li, J., Zhang, J., Gao, J., Lu, B., & Huang, C. (2013). GADD45β mediates p53 protein degradation via Src/PP2A/MDM2 pathway upon arsenite treatment. Cell Death and Disease, 4(5). https://doi.org/10.1038/cddis.2013.162

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