The DOI matches its Crossref record; 63 of the 70 references it cites were found in a registry or an index.
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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“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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Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis
Hanahan, D., & Folkman, J. (1996) · Cell · doi:10.1016/s0092-8674(00)80108-7 · Cited by 6,885
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
Self-citationThe tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis
Shweiki, D., Itin, A., Soffer, D., & Keshet, E. (1992) · Nature · doi:10.1038/359843a0 · Cited by 4,617
The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990) · Cell · doi:10.1016/0092-8674(90)90409-8 · Cited by 3,995
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
Forsythe, J. A., Jiang, B.-H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., & Semenza, G. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4604 · Cited by 3,981
Self-citationKim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S., & Ferrara, N. (1993) · Nature · doi:10.1038/362841a0 · Cited by 3,605
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · cited 1×
“…ligase and is itself a target for Ub-mediated degradation via its interaction with Mdm2 (Momand et al. 1992; Barak et al. 1993; Wu et al. 1993; Haupt et al. 1997; Honda et al. 1997; Kubbutat et al. 1997), this raised the possibility that HIF-1a is recruited to Mdm2 via its interaction with p53.”
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Flagged first, then by citations
7 of the 70 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- Kubbutat, 1997, Regulation of p53 stability by Mdm2., Nature, 387, 299, 10.1038/387299a0 · DOI · Paper page
- Ravi, 1998, p53-mediated repression of nuclear factor κ-B RelA via the transcriptional integrator p 300., Cancer Res., 58, 4531
- Zhong, 1999, Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases., Cancer Res., 59, 5830
Cited by
Sorted by citations
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Self-citationHypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177
Tumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
The STATs of cancer — new molecular targets come of age
Yu, H., & Jove, R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1275 · Cited by 2,278
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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