Title: GADD45β mediates p53 protein degradation via Src/PP2A/MDM2 pathway upon arsenite treatment.
Authors: Yu, Y; Huang, H; Li, J; Zhang, J; Gao, J; Lu, B; Huang, C
Published In Cell Death Dis, (2013 May 16)
Abstract: Growth arrest and DNA-damage-inducible, beta (GADD45β) has been reported to inhibit apoptosis via attenuating c-Jun N-terminal kinase (JNK) activation. We demonstrated here that GADD45β 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 GADD45β 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.
PubMed ID: 23681232
MeSH Terms: Animals; Antigens, Differentiation/genetics; Antigens, Differentiation/metabolism*; Apoptosis/drug effects*; Arsenites/toxicity*; HCT116 Cells; Humans; JNK Mitogen-Activated Protein Kinases/metabolism; Mice; Phosphorylation/drug effects; Protein Phosphatase 2/metabolism*; Proto-Oncogene Proteins c-mdm2/metabolism*; Tumor Suppressor Protein p53/metabolism*; src-Family Kinases/metabolism*