Inactivation of the p53-homologue p73 by the mdm2-oncoprotein

Dobbelstein, Matthias; Wienzek, Sandra; König, Claudia; Roth, Judith

doi:10.1038/sj.onc.1202512

Cited by 161Cancer-related Molecular PathwaysHeat shock proteins researchUbiquitin and proteasome pathways

Inactivation of the p53-homologue p73 by the mdm2-oncoprotein

Dobbelstein, Matthias, Wienzek, Sandra, König, Claudia, Roth, Judith·1999·Oncogene

DOI 10.1038/sj.onc.1202512

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Abstract

The p73beta protein shares structural and functional similarities with the tumor suppressor gene product p53. Both proteins activate transcription from p53-responsive promoters. p53's activity is antagonized by the mdm2 protein (also termed hdm2 in human cells). Complex formation between p53 and mdm2 results in p53's transcriptional inactivation and destabilization. Here we show that overexpression of mdm2 reduces p73beta's ability to activate transcription, too. The mdm2 protein forms a specific complex with p73beta in vitro with an efficiency comparable to p53-binding. Further, both p73beta and p53 relocalize a transport-defective mutant of mdm2 from the cytoplasm to the nucleus, arguing that complex formation occurs in vivo as well. Mutational analysis suggests that the interaction between p73beta and mdm2 follows structural principles analogous to the p53-mdm2-complex. Whereas p53 is destabilized in the presence of mdm2, the amount of intracellular p73beta was not detectably reduced by mdm2. The carboxyterminal RING finger domain of mdm2 was found to be required to reduce the intracellular abundance of p53, but it was dispensable for transcriptionally inactivating either p53 or p73beta. Our results suggest that the autoregulatory feedback loop between p53 and mdm2 also controls p73's activity, but that mdm2-mediated protein degradation is unique to p53.

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Mdm2 does not ubiquitinate p73α.
“While p53 and p73α can both interact with Mdm2 in the same N-terminal hydrophobic pocket (12), Mdm2 does not ubiquitinate p73α (44–46).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [44]

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Authors: Dobbelstein, M., Wienzek, S., König, C., & Roth, J.
Affiliations: Philipps University of Marburg (DE)
ORCID: Dobbelstein, Matthias
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 1999-03-25
Volume: 18
Issue: 12
Pages: 2101-2106
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/sj.onc.1202512
OpenAlex: W2312957642
Cited by: 161
References: 40
Citations by year: 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 4 · 2015: 6 · 2014: 6 · 2013: 4 · 2012: 5
FWCI: 7.98
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: p53, MDM2, transcriptional inactivation, protein-protein interaction, RING domain, protein degradation, autoregulatory loop, tumor suppressor proteins, nuclear translocation
MeSH terms: Tumor Protein p73, Biological Transport, Cell Compartmentation, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-mdm2

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Inactivation of the p53-homologue p73 by the mdm2-oncoprotein

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