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Cited by 71Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

MdmX inhibits ARF mediated Mdm2 sumoylation

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Ghosh, Mithua, Weghorst, Karen, Berberich, Steven J.·2005·Cell Cycle
DOI 10.4161/cc.4.4.1597
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Abstract

Mdm2, by virtue of an intrinsic E3 ubiquitin ligase activity, is capable of autoubiquitination and the ubiquitination of the p53 tumor suppressor protein. Additionally, Hdm2 has been reported to undergo a p14ARF-dependent sumoylation with concurrent Hdm2 stabilization. In this present work, we report that MdmX can undergo ARF-mediated sumoylation similar to that reported for Mdm2. When coexpressed, MdmX overexpression results in a dose-dependent inhibition of Mdm2 sumoylation and a concurrent increase in Mdm2 ubiquitination. This switch from Mdm2 sumoylation to Mdm2 ubiquitination may explain the destablization of Mdm2 previously observed in cells overexpressing both ARF and MdmX. Given that MdmX can heterodimerize with Mdm2 and separately associate with ARF we employed a series of MdmX mutants to examine how MdmX blocks Mdm2 sumoylation. A MdmX miniprotein capable of binding to ARF, but not p53 or Mdm2 was able to competitively inhibit Mdm2 sumoylation and reverse ARF mediated activation of p53 transactivation. Taken together, these results demonstrate that MdmX can affect post-translational modification and stability of Mdm2 and p53 activity through interaction with ARF.

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  • Mdm2 and Mdmx bind many other proteins, including proteins involved in development, morphogenesis, and tumorigenesis.

    “However, both Mdm2 and Mdmx interact with many other proteins, including those involved in development, morphogenesis and tumorigenesis (Table 2; [81–92]).”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [89]

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Authors
Ghosh, M., Weghorst, K., & Berberich, S. J.
Affiliations
Wright State University (US)
Venue
Cell Cycle
Publisher
Informa UK Limited
Published
2005-01-28
Volume
4
Issue
4
Pages
597-601
ISSN
  • 1538-4101 (ISSN-L)
  • 1551-4005
DOI
10.4161/cc.4.4.1597
OpenAlex
W4322696828
Cited by
71
References
2
Citations by year
2025: 1 · 2023: 1 · 2021: 3 · 2020: 2 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 2
FWCI
3.89
Type
journal article
Language
en
Open access
Locations
  • Cell Cycle (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01CA064430)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
MDMX, MDM2, p14ARF, SUMOylation, ubiquitination, p53, E3 ubiquitin ligase, protein stability, protein-protein interaction, p53 transactivation, post-translational modification
MeSH terms
Cell Cycle, Gene Expression Regulation, Humans, Luciferases, Nuclear Proteins, Plasmids, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Transfection, Blotting, Western, Transcriptional Activation, Genes, p53, Tumor Suppressor Protein p53, Genes, Reporter, Dimerization, Cyclin-Dependent Kinase Inhibitor p16, Ubiquitin, Tumor Suppressor Protein p14ARF, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2, Smad Proteins

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