Cited by 967Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer-related Molecular Pathways

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Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α

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Ravi, Rajani, Mookerjee, Bijoyesh, Bhujwalla, Zaver M., Sutter, Carrie Hayes, Artemov, Dmitri, Zeng, Qinwen, Dillehay, Larry E., Madan, Ashima, Semenza, Gregg L., Bedi, Atul·2000·Genes & Development

DOI 10.1101/gad.14.1.34

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Abstract

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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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)
ORCID: Bhujwalla, Zaver M.
Artemov, Dmitri
Semenza, Gregg L.
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
DOI: 10.1101/gad.14.1.34
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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Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α

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