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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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
Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
Role for the p53 homologue p73 in E2F-1-induced apoptosis
Irwin, M. S., Marín, M. C., Phillips, A. C., Seelan, R. S., Smith, D. I., Liu, W., Flores, E. R., Tsai, K. Y., Jacks, T., Vousden, K. H., et al. (2000) · Nature · doi:10.1038/35036614 · Cited by 710
Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507493103 · Cited by 708
Inactivation of the p53 pathway in retinoblastoma
Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., et al. (2006) · Nature · doi:10.1038/nature05194 · Cited by 595
AIS is an oncogene amplified in squamous cell carcinoma
Hibi, K., Trink, B., Patturajan, M., Westra, W. H., Caballero, O. L., Hill, D. E., Ratovitski, E. A., Jen, J., & Sidransky, D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.10.5462 · Cited by 464
p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis
Rocco, J. W., Leong, C., Kuperwasser, N., DeYoung, M. P., & Ellisen, L. W. (2006) · Cancer Cell · doi:10.1016/j.ccr.2005.12.013 · Cited by 435
Chemosensitivity linked to p73 function
Irwin, M. S., Kondo, K., Marín, M. C., Cheng, L. S., Hahn, W. C., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00078-3 · Cited by 406
Iwakuma, T., & Lozano, G. (2003) · PubMed · Cited by 390
MDM2 suppresses p73 function without promoting p73 degradation
Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G., Oren, M., Chen, J., & Lu, H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3257 · Cited by 334
Cited by
Sorted by citations
The role of p53 in cancer drug resistance and targeted chemotherapy
Hientz, K., Mohr, A., Bhakta-Guha, D., & Efferth, T. (2016) · Oncotarget · doi:10.18632/oncotarget.13475 · Cited by 612
Dutt, S., Narla, A., Lin, K. I., Mullally, A., Abayasekara, N., Megerdichian, C., Wilson, F. H., Currie, T., Khanna‐Gupta, A., Berliner, N., et al. (2010) · Blood · doi:10.1182/blood-2010-07-295238 · Cited by 410
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381
Targeting the MDM2-p53 Interaction for Cancer Therapy
Shangary, S. K., & Wang, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5136 · Cited by 372
p53 Family and Cellular Stress Responses in Cancer
Pflaum, J., Schlosser, S., & ller, M. M. ⁄. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00285 · Cited by 309
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
