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BMK1 is involved in the regulation of p53 through disrupting the PML–MDM2 interaction

Oncogene volume 32, pages 3156–3164 (2013)Cite this article

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Abstract

Promyelocytic leukemia protein (PML) modulates the p53 tumor suppressor through its interaction with p53 and MDM2. We found that activated big MAP kinase 1 (BMK1) preferentially associates with PML isoform IV and disrupts PML–MDM2 interaction. Doxorubicin, a common chemotherapeutic agent, is known to promote PML-mediated p53 activation in part by promoting PML-dependent MDM2 nucleolar sequestration. We discovered that BMK1 deactivation coupled with doxorubicin synergistically enhanced MDM2 nucleolar sequestration and, consequently, promoted PML-mediated p53 upregulation leading to tumor cell apoptosis in vitro and tumor regression in vivo. Collectively, these results not only suggest that BMK1 activity has a role in suppressing p53 by blocking the interaction between PML and MDM2, but also implicate that pharmacological BMK1 inhibitor should significantly enhance the anticancer capacity of doxorubicin-based chemotherapy.

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Acknowledgements

We thank Dr Giovanni Blandino, Dr Myung Kim and Dr Pier Paolo Pandolfi for generously providing the PML null and control cell lines. This work was supported by the National Institutes of Health [CA079871 and CA114059 to JDL] and by the funds from the Tobacco-Related Disease, Research Program of the University of California [19XT-0084 to JDL].

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Authors and Affiliations

  1. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA

    Q Yang, R Chen & J D Lee

  2. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA

    L Liao & J R Yates III

  3. Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    X Deng & N S Gray

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  1. Q Yang
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  2. L Liao
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Correspondence to J D Lee.

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Yang, Q., Liao, L., Deng, X. et al. BMK1 is involved in the regulation of p53 through disrupting the PML–MDM2 interaction. Oncogene 32, 3156–3164 (2013). https://doi.org/10.1038/onc.2012.332

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