The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
Mdm2 promotes the rapid degradation of p53
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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In the citing paper
“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 the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“Upon cell stress, this interaction is disrupted leading to increased levels of active, nuclear-localized p53.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [64]
In the citing paper
“However, MDM2 is one of the most upregulated E3 ligases in cancer, leading to constant removal of p53 [63–65].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [64]
In the citing paper
“MDM2 binds the p53 transactivation domain, leading to the inhibition of p53 function, nuclear export and degradation under physiological conditions.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [64]
In the citing paper
“Mouse double minute 2 homolog (MDM2) is an oncoprotein with E3 ligase activity that targets the tumour suppressor p53 for ubiquitination.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [64]
Citations
Cites
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The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
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Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
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Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
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In vivo ubiquitination and proteasome-mediated degradation of p53(1).
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Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines.
Bártek, J., Iggo, R. D., Gannon, J., & Lane, D. P. (1990) · PubMed · Cited by 603
Interaction between the retinoblastoma protein and the oncoprotein MDM2
Xiao, Z.-X., Chen, J., Levine, A. J., Modjtahedi, N., Xing, J. W., Sellers, W. R., & Livingston, D. M. (1995) · Nature · doi:10.1038/375694a0 · Cited by 586
p53 in growth control and neoplasia
Gottlieb, T. M., & Oren, M. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(95)00019-c · Cited by 483
Self-citation
Cited by
Sorted by citations
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840
Mechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,184
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312
Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization
Diehl, J. A., Cheng, M., Roussel, M. F., & Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.22.3499 · Cited by 2,130
DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100
Metadata
- Authors
- Haupt, Y., Maya, R., Kazaz, A., & Oren, M.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Weizmann Institute of Science (IL)
- Venue
- Nature
- Published
- 1997-05
- Volume
- 387
- Issue
- 6630
- Pages
- 296-299
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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