Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1α and Hdm2
Abstract
Hdm2 is elevated in numerous types of malignancies and is thought to impede the function of wild-type p53. Reactivation of p53 by disrupting the association with Hdm2 was the impetus for the development of Nutlin3. Although regulation of p53 has been the central focus of Hdm2 activity, it also binds other proteins through its p53-binding domain. Here, we show that hypoxia-inducible factor 1alpha (HIF1alpha) binds to Hdm2 in the domain designated to bind p53. HIF1alpha and p53 share a conserved motif that is required to bind Hdm2. Distinct complexes form between Hdm2-HIF1alpha and Hdm2-p53 as determined by immunoprecipitation of nuclear extracts and in vitro. The Hdm2 antagonist Nutlin3 prevents the association between Hdm2 and HIF1alpha. The vascular endothelial growth factor (VEGF) gene is a transcriptional target of HIF1alpha, and under normoxic or hypoxic conditions, Hdm2 increases HIF1alpha activity to induce VEGF production. Blocking the association of Hdm2 and HIF1alpha by Nutlin3, or ablating Hdm2 expression, diminished the level of VEGF under conditions of normoxia or hypoxia. Our findings establish a unique role for Nutlin3 in attenuating VEGF induction by preventing the association of Hdm2 with HIF1alpha.
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Nutlin3a binds the N-terminal hydrophobic pocket of MDM2 and prevents MDM2 from interacting with p53 and other signal transducers such as p73α, E2F1, Rb, and HIF-1α.
“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 [21]
Dosing regimens that build on front-line chemotherapy for GBM are not well described.
“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 [21]
Nutlin-3a also inhibits binding of p73α, E2F1, and Hif-1α to the N-terminal hydrophobic pocket of Mdm2.
“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 [13]
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- Authors
- LaRusch, G. A., Jackson, M. W., Dunbar, J. D., Warren, R. S., Donner, D. B., & Mayo, L. D.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Cleveland Clinic (US)
- Indiana University School of Medicine (US)
- University of California, San Francisco (US)
- Venue
- Cancer Research
- Published
- 2007-01-15
- Volume
- 67
- Issue
- 2
- Pages
- 450-454
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2142605244
- Cited by
- 89
- References
- 21
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 6 · 2012: 8
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (F32HL072661)
- National Cancer Institute (CA109262, R01CA109262)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- MDM2, HIF-1α, p53, vascular endothelial growth factor, hypoxia, protein-protein interaction, p53-binding domain, transcriptional regulation
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Imidazoles, Piperazines, Protein Binding, Rabbits, Recombinant Proteins, Transfection, Tumor Suppressor Protein p53, Sequence Alignment, Conserved Sequence, Protein Structure, Tertiary, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2, Hypoxia-Inducible Factor 1, alpha Subunit
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