Cited by 33Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2

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Ohtsubo, Chihiro, Shiokawa, Daisuke, Kodama, Masami, Gaiddon, Christian, Nakagama, Hitoshi, Jochemsen, Aart G., Taya, Yoichi, Okamoto, Koji·2009·Cancer Science

Abstract

The mdm2 and mdmx oncogenes play essential yet nonredundant roles in synergistic inactivatiosn of p53. However, the biochemical mechanism by which Mdmx synergizes with Mdm2 to inhibit p53 function remains obscure. Here we demonstrate that, using nonphosphorylatable mutants of Mdmx, the cooperative inhibition of p53 by Mdmx and Mdm2 was associated with cytoplasmic localization of p53, and with an increase of the interaction of Mdmx to p53 and Mdm2 in the cytoplasm. In addition, the Mdmx mutant cooperates with Mdm2 to induce ubiquitination of p53 at C-terminal lysine residues, and the integrity of the C-terminal lysines was partly required for the cooperative inhibition. The expression of subcellular localization mutants of Mdmx revealed that subcellular localization of Mdmx dictated p53 localization, and that cytoplasmic Mdmx tethered p53 in the cytoplasm and efficiently inhibited p53 activity. RNAi-mediated inhibition of Mdmx or introduction of the nuclear localization mutant of Mdmx reduced cytoplasmic retention of p53 in neuroblastoma cells, in which cytoplasmic sequestration of p53 is involved in its inactivation. Our data indicate that cytoplasmic tethering of p53 mediated by Mdmx contributes to p53 inactivation in some types of cancer cells.

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Crossref · 10.1111/j.1349-7006.2009.01180.x

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  • Mdm2 promotes translocation of p53 from the nucleus to the cytoplasm, and Mdmx may modulate this process.

    “Interestingly, Mdm2 has been reported to promote translocation of p53 from the nucleus to the cytoplasm, and Mdmx may modulate this process [4].”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [4]

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Authors
Ohtsubo, C., Shiokawa, D., Kodama, M., Gaiddon, C., Nakagama, H., Jochemsen, A. G., Taya, Y., & Okamoto, K.
Affiliations
  • Japan Science and Technology Agency (JP)
  • National University of Singapore (SG)
  • Inserm (FR)
  • Leiden University Medical Center (NL)
Corresponding author
  • Taya, Yoichi
  • Okamoto, Koji
Venue
Cancer Science
Publisher
Wiley
Published
2009-06-10
Volume
100
Issue
7
Pages
1291-1299
ISSN
  • 1347-9032 (ISSN-L)
  • 1349-7006
OpenAlex
W2041779012
Cited by
32
References
43
Citations by year
2024: 1 · 2023: 1 · 2021: 3 · 2020: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 2
FWCI
1.66
Type
journal article
Language
en
Open access
Locations
  • Cancer Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders
Foundation for Promotion of Cancer Research
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
p53 inactivation, MDMX, MDM2, p53 ubiquitination, protein-protein interaction, neuroblastoma cells, tumor suppressor regulation
MeSH terms
Amino Acid Sequence, Cytoplasm, Humans, Molecular Sequence Data, Phosphorylation, Tumor Suppressor Protein p53, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2

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