Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
Open accessAbstract
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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Beyond canonical HRE-driven transcription, HIF isoforms differentially affect signaling pathways by interacting with non-PAS proteins such as p53, c-MYC, β-catenin, and the Notch intracellular domain.
“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]
The section ‘p53 promotes ubiquitin-dependent [degradation] of HIF-1α’ reports that HIF-1α co-immunoprecipitates with p53, supporting p53 as an interaction partner. The paper shows p53 promoting HIF-1α degradation, however; it does not establish that HIF isoforms differentially modulate signaling through this interaction. The other listed proteins are not the part this citation supports. (LLM, conf=0.84)
Experimental — accuracy not yet measuredp53 can promote Mdm2-mediated degradation of HIF-1α.
“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
miR-17 mediates cellular response to diverse stimuli by targeting closely related signaling pathways.
“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]
MDM2 can ubiquitinate and degrade HIF-1α through the proteasome pathway.
“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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“Intriguingly, p53 can also promote Mdm2-mediated degradation of HIF-1α (Ravi et al., 2000).”
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Expression of hypoxia-inducible factor 1? in brain tumors
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TSC2 regulates VEGF through mTOR-dependent and -independent pathways
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Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity.
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Regulation of angiogenesis by hypoxia-inducible factor 1
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Self-citationHypoxia-responsive transcription factors
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P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis
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Activation of the HIF pathway in cancer
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Tie receptors: new modulators of angiogenic and lymphangiogenic responses
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Regulation of Metabolism by Hypoxia-Inducible Factor 1
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- 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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