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

Academic Article
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Overview

authors

  • Yang, Q.
  • Liao, L.
  • Deng, X.
  • Chen, R.
  • Gray, N. S.
  • Yates III, John
  • Lee, Jiing-Dwan

publication date

  • June 2013

journal

  • Oncogene  Journal

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.

subject areas

  • Animals
  • Antibiotics, Antineoplastic
  • Cell Line, Tumor
  • Doxorubicin
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase 7
  • Neoplasm Transplantation
  • Nuclear Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins c-mdm2
  • RNA Interference
  • RNA, Small Interfering
  • Transcription Factors
  • Transcriptional Activation
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
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Research

keywords

  • BMK1
  • PML
  • p53
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Identity

PubMed Central ID

  • PMC3493705

International Standard Serial Number (ISSN)

  • 0950-9232

Digital Object Identifier (DOI)

  • 10.1038/onc.2012.332

PubMed ID

  • 22869143
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Additional Document Info

start page

  • 3156

end page

  • 3164

volume

  • 32

issue

  • 26

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