Mdm2 promotes the rapid degradation of p53

Haupt, Ygal; Maya, Ruth; Kazaz, Anat; Oren, Moshe

doi:10.1038/387296a0

Cited by 4,506Cancer-related Molecular PathwaysHeat shock proteins researchUbiquitin and proteasome pathways

Mdm2 promotes the rapid degradation of p53

Haupt, Ygal, Maya, Ruth, Kazaz, Anat, Oren, Moshe·1997·Nature

DOI 10.1038/387296a0

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Abstract

The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.

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The best known feedback loop uses MDM2, a p53 target gene that encodes a ubiquitin ligase, which mediates degradation of p53.
“The best known feedback loop uses MDM2, a p53 target gene that encodes a ubiquitin ligase, which mediates degradation of p53.14, 15, 217”
From Census and evaluation of p53 target genes (2017) · cites this paper as [217]
In undamaged cells, p53 protein levels are maintained at minimal levels due to prompt proteasome-targeting polyubiquitination by the Mdm2 E3 ubiquitin ligase.
“In undamaged cells, p53 protein levels are maintained at minimal levels due to prompt proteasome-targeting polyubiquitination by the Mdm2 E3 ubiquitin ligase (Haupt et al., 1997; Honda et al., 1997; Kubbutat et al., 1997).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Haupt et al., 1997
Mdm2 is an E3 ubiquitin ligase that targets p53 for proteasomal degradation.
“Mdm2 is a E3 ubiquitin ligase that targets p53 for degradation by the proteasome (7)”
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 [7]
Mdm2 and Mdm4 can reduce p53 activity and permit cells to survive and proliferate.
“Cellular proteins such as Mdm2 (MIM#164785) and Mdm4 (MIM#602704) can dampen p53 activity and allow the cell to live and propagate.”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Haupt, et al., 1997
Mdm2 is an E3 ubiquitin ligase that ubiquitylates p53 and targets it for degradation.
“Mdm2 is an E3 ubiquitin ligase that ubiquitylates and targets p53 for degradation (Haupt, et al., 1997; Honda, et al., 1997; Kubbutat, et al., 1997).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Haupt, et al., 1997

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Authors: Haupt, Y., Maya, R., Kazaz, A., & Oren, M.
Affiliations: Hebrew University of Jerusalem (IL)
Weizmann Institute of Science (IL)
ORCID: Haupt, Ygal
Maya, Ruth
Oren, Moshe
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1997-05
Volume: 387
Issue: 6630
Pages: 296-299
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/387296a0
OpenAlex: W2082979850
Cited by: 4,506
References: 29
Citations by year: 2026: 114 · 2025: 117 · 2024: 136 · 2023: 150 · 2022: 163 · 2021: 167 · 2020: 172 · 2019: 131 · 2018: 128 · 2017: 139 · 2016: 138 · 2015: 122 · 2014: 188 · 2013: 147 · 2012: 197
FWCI: 78.92
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
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: MDM2, p53, p53 degradation, protein stabilization, p53-MDM2 interaction, DNA damage response, tumour suppressor, autoregulatory loop, mutant p53
MeSH terms: Animals, HeLa Cells, Humans, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, RNA, Messenger, Transfection, Tumor Cells, Cultured, Down-Regulation, Tumor Suppressor Protein p53, Mice, Proto-Oncogene Proteins c-mdm2

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Mdm2 promotes the rapid degradation of p53

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