Cited by 361Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

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HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53

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Linares, Laëtitia K., Hengstermann, Arnd, Ciechanover, Aaron, Müller, Stefan, Scheffner, Martin·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.2030930100PMC PMC218704

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Abstract

The RING finger proteins HdmX and Hdm2 share significant structural and functional similarity. Hdm2 is a member of the RING finger family of ubiquitin-protein ligases E3 and targets the tumor suppressor protein p53 for degradation. Although HdmX also binds to p53, HdmX does not induce p53 degradation. Moreover, HdmX has been reported to interfere with p53 degradation in overexpression experiments. To obtain insight into the mechanism by which HdmX interferes with p53 degradation, we studied the effect of HdmX on the E3 activity of Hdm2 in vitro. Surprisingly, this revealed that HdmX stimulates Hdm2-mediated ubiquitination of p53 and that HdmX facilitates ubiquitination of Hdm2 and vice versa. In addition, down-regulation of HdmX expression within cells results in the accumulation of both p53 and Hdm2. Because HdmX alone does not have appreciable E3 activity, these data indicate that HdmX acts as a stimulator, rather than as an inhibitor, of the E3 activity of Hdm2 and that, at least under certain conditions, HdmX is actively involved in the degradation of both p53 and Hdm2.

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Authors: Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M.
Affiliations: Center for Biochemistry, Medical Faculty, and Center for Molecular Medicine, University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany; and Department of Biochemistry and The Rappaport Family Institute for Research in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
Technion – Israel Institute of Technology (IL)
ORCID: Ciechanover, Aaron
Müller, Stefan
Scheffner, Martin
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-09-24
Volume: 100
Issue: 21
Pages: 12009-12014
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.2030930100
PMC: PMC218704
OpenAlex: W2046135777
Cited by: 361
References: 38
Citations by year: 2026: 2 · 2025: 9 · 2024: 5 · 2023: 11 · 2022: 15 · 2021: 17 · 2020: 17 · 2019: 14 · 2018: 10 · 2017: 16 · 2016: 16 · 2015: 12 · 2014: 30 · 2013: 19 · 2012: 30
FWCI: 4.81
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
KOPS (University of Konstanz) (submittedVersion)
Funders: German-Israeli Foundation for Scientific Research and Development
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: HDMX, MDM2, p53 degradation, ubiquitination, E3 ubiquitin ligase, RING finger protein, protein degradation, tumor suppressor, protein-protein interaction, p53 accumulation
MeSH terms: Amino Acid Sequence, Base Sequence, Cell Line, Humans, Molecular Sequence Data, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Tumor Suppressor Protein p53, Ubiquitin, RNA, Small Interfering, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-mdm2, In Vitro Techniques

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HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53

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