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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Cell Line, Tumor
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Doxorubicin / pharmacology
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Enzyme Activation
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HeLa Cells
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Humans
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Mice
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Mitogen-Activated Protein Kinase 7 / genetics
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Mitogen-Activated Protein Kinase 7 / metabolism*
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Neoplasm Transplantation
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Nuclear Proteins / metabolism*
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Promyelocytic Leukemia Protein
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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RNA Interference
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RNA, Small Interfering
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Transcription Factors / metabolism*
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Transcriptional Activation
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Transplantation, Heterologous
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / metabolism*
Substances
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Antibiotics, Antineoplastic
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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Protein Isoforms
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RNA, Small Interfering
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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PML protein, human
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Doxorubicin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Mitogen-Activated Protein Kinase 7