The DOI matches its Crossref record; 30 of the 31 references it cites were found in a registry or an index.
HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function
Abstract
Nutlin-3, a small molecule inhibitor, activates p53 by disrupting p53-HDM2 association. In this study, we found that Nutlin-3 suppressed cell growth and induced apoptosis in the absence of wild-type p53, suggesting a p53-independent mechanism for Nutlin-3-induced cell death. Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. We demonstrate that Nutlin-3 inhibits endogenous binding between the proapoptotic p73 isoform TAp73alpha and HDM2 in p53-null cells. Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. p73 knockdown by siRNA results in rescue of Nutlin-3-treated cells, indicating that Nutlin-3-induced apoptosis is, at least in part, p73 dependent. In addition, Nutlin-3 treatment increases TAp73alpha protein levels with prolongation of p73 half-life. These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated.
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In the citing paper
“The MDM2 protein–protein interaction (PPI) inhibitor nutlin3a binds to the N-terminal hydrophobic pocket of MDM2 and blocks interaction of MDM2 with not only p53 but also a number of other key signal transducers, including p73α, E2F1, Rb, and HIF-1α”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [22]
In the citing paper
“information on dosing regimens that build upon front-line chemotherapy for GBM is lacking.19,21,22,34,43,45”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [22]
In the citing paper
“Nutlin-3a also inhibits the binding of the p73 isoform p73α, as well as E2F1 and hypoxia inducible factor 1α (Hif-1α), to the N-terminal hydrophobic pocket of Mdm2 (11–13).”
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 [12]
In the citing paper
“Lau and colleagues showed that when cells were treated with Nutlin-3a, the binding of p73α to Mdm2 was inhibited, leading to p73α-mediated induction of pro-apoptotic downstream targets and increased apoptosis in cells lacking wild-type p53 (12).”
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 [12]
In the citing paper
“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 [12]
In the citing paper
“These data are consistent with previous reports indicating that p73α can directly bind to the Mdm2 promoter and increase Mdm2 gene expression (12, 47).”
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 [12]
In the citing paper
“Blockade of the binding of Mdm2 to p73α by Nutlin-3a increases the pool of p73α available to transcriptionally activate pro-apoptotic gene expression and promote apoptosis in mutant p53 and p53 null cells (12).”
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 [12]
Citations
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Metadata
- Authors
- Lau, L. M. S., Nugent, J. K., Zhao, X., & Irwin, M. S.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Irwin, M S
- Venue
- Oncogene
- Published
- 2007-08-13
- Volume
- 27
- Issue
- 7
- Pages
- 997-1003
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2029865335
- Cited by
- 182
- References
- 31
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 2 · 2022: 10 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 6 · 2012: 18
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canada Research Chairs
- Terry Fox Foundation
- Hospital for Sick Children
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- Nutlin-3, p73, MDM2, p53-independent apoptosis, Noxa, PUMA, p21, transcriptional activation, p53-null cells, p53 inactivation, cancer therapy
- MeSH terms
- Bone Neoplasms, DNA-Binding Proteins, Humans, Imidazoles, Nuclear Proteins, Piperazines, Protein Binding, Proto-Oncogene Proteins, Osteosarcoma, Transcription, Genetic, Protein Biosynthesis, Immunoblotting, Tumor Suppressor Protein p53, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Tumor Suppressor Proteins, RNA, Small Interfering, HCT116 Cells, Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-mdm2
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