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Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
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The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1α levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1α in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.
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“Apart from canonical HRE-mediated transcription, the HIF isoforms differentially modulate signaling pathways through interaction with proteins that do not contain PAS domains, such p53, the c-MYC proto-oncogene, β-catenin and the Notch intracellular domain (Fig. 2A) [11–15].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [11]
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“Intriguingly, p53 can also promote Mdm2-mediated degradation of HIF-1α (Ravi et al., 2000).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Ravi et al., 2000
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“It has been proposed that MDM2 can also ubiquitinate and degrade HIF-1α through the proteasome pathway”
From Stress Response of Glioblastoma Cells Mediated by miR-17-5p Targeting PTEN and the Passenger Strand miR-17-3p Targeting MDM2 (2012) · cites this paper as [56]
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“which raises the possibility that miR-17 mediates cellular response to diverse stimuli by targeting closely related signaling pathways [56].”
From Stress Response of Glioblastoma Cells Mediated by miR-17-5p Targeting PTEN and the Passenger Strand miR-17-3p Targeting MDM2 (2012) · cites this paper as [56]
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Metadata
- Authors
- Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-01-01
- Volume
- 14
- Issue
- 1
- Pages
- 34-44
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W4294718043
- Semantic Scholar
- 5c0770cda1be256df47794076979768b0350af33
- Cited by
- 967
- References
- 70
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 35 · 2023: 28 · 2022: 35 · 2021: 35 · 2020: 33 · 2019: 25 · 2018: 30 · 2017: 25 · 2016: 35 · 2015: 41 · 2014: 36 · 2013: 34 · 2012: 32
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Funders
- U.S. Department of Defense
- American Cancer Society
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- tumor angiogenesis, p53, hypoxia-inducible factor-1α, MDM2, ubiquitination, proteasomal degradation, vascular endothelial growth factor, hypoxia, neovascularization, tumor xenografts, angiogenic switch, tumor suppressor
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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.
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