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

Growth arrest and DNA-damage-inducible, beta (GADD45 beta) has been reported to inhibit apoptosis via attenuating c-Jun N-terminal kinase (JNK) activation. We demonstrated here that GADD45 beta mediated its anti-apoptotic effect via promoting p53 protein degradation following arsenite treatment. We found that p53 protein expression was upregulated in GADD45 beta-/-cells upon arsenite exposure as compared with those in GADD45 beta +/+ cells. Further studies showed that GADD45 beta attenuated p53 protein expression through Src/protein phosphatase 2A/murine double minute 2-dependent p53 protein-degradation pathway. Moreover, we identified that GADD45 beta-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 GADD45 beta-/-cells under same experimental conditions. Collectively, our results demonstrate a novel molecular mechanism responsible for GADD45 beta protection of arsenite-exposed cells from cell death, which provides insight into our understanding of GADD45 beta 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.