title: BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction.
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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Liao
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.forename: N S
authors.initials: NS
authors.lastname: Gray
authors.forename: J R
authors.initials: JR
authors.lastname: Yates
authors.forename: J D
authors.initials: JD
authors.lastname: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D048054:Mitogen-Activated Protein Kinase 7