MDM2 suppresses p73 function without promoting p73 degradation
Open accessAbstract
The newly identified p53 homolog p73 can mimic the transcriptional activation function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo and in vitro. Wild-type but not mutant MDM2, expressed in human p53 null osteosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driven by the MDM2 promoter-derived p53RE motif as measured in transient-transfection and chloramphenicol acetyltransferase assays and also inhibited p73-induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73alpha and p73beta stimulated the expression of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activated by p73 and, in turn, negatively regulates the function of this activator through a mechanism distinct from that used for p53 inactivation.
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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 [45]
Mdm2 sequesters p73α and thereby prevents downstream p73α-mediated signaling.
“Rather, Mdm2 sequesters p73α thereby preventing downstream p73α-mediated signaling (45).”
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 [45]
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- Authors
- Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G., Oren, M., Chen, J., & Lu, H.
- Affiliations
- Oregon Health & Science University (US)
- Louisiana State University (US)
- Harvard University (US)
- Weizmann Institute of Science (IL)
- Howard Hughes Medical Institute (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1999-05
- Volume
- 19
- Issue
- 5
- Pages
- 3257-3266
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC84120
- OpenAlex
- W2106031335
- Cited by
- 334
- References
- 65
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 5 · 2015: 13 · 2014: 10 · 2013: 11 · 2012: 12
- FWCI
- 13.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01 CA 79721-01, R01CA079721)
- 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 › Cell death mechanisms and regulation
- Keywords
- MDM2, p73, p53, CBP/p300, transcriptional activation, autoregulatory loop, p53 response elements, apoptosis, protein-protein interaction, p73alpha, p53-null cells
- MeSH terms
- Tumor Protein p73, DNA-Binding Proteins, Feedback, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Mutation, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Recombinant Proteins, Transcription, Genetic, Tumor Cells, Cultured, Transcriptional Activation, Trans-Activators, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Apoptosis, Genes, Reporter, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-mdm2
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