Abstract
p53 stability is regulated by HDM2, a RING domain protein that acts as an E3 ligase to ubiquitinate p53 and target its degradation. Phosphorylation of HDM2 on serine 166 by AKT has been shown to enhance HDM2 activity and promote the degradation of p53. Here, we show that MAPKAP kinase 2 (MK2) can phosphorylate HDM2 on serine 157 and 166 in vitro. Treatment of cells with anisomycin, which activates MK2, also results in phosphorylation of HDM2 on serine 157 and 166 in vivo. Mutation of the MK2 phosphorylation sites in HDM2 to aspartic acid renders HDM2 slightly more active in the degradation of p53, and mouse cells deficient for MK2 show reduced Mdm2 phosphorylation and elevated levels of p53 protein. Together, our results suggest that MK2 may act to dampen the extent and duration of the p53 response.
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Acknowledgements
We are extremely grateful to Brian Hemmings for the mouse anti-Mdm2-P-ser166 antibody. This work was funded by Cancer Research UK, the National Cancer Institute and the Deutsche Forschungsgemeinschaft.
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Weber, H., Ludwig, R., Morrison, D. et al. HDM2 phosphorylation by MAPKAP kinase 2. Oncogene 24, 1965–1972 (2005). https://doi.org/10.1038/sj.onc.1208389
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DOI: https://doi.org/10.1038/sj.onc.1208389
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