BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction.
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Yang Q, Liao L, Deng X, Chen R, Gray NS, Yates JR 3rd, Lee JD
BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction.
Oncogene. 2013 Jun 27;32(26):3156-64. doi: 10.1038/onc.2012.332. Epub 2012 Aug 6.
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- 22869143 [ View in PubMed]
- 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.