Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
10.1101/gad.14.1.34
Crossref journal-article
Cold Spring Harbor Laboratory
Genes & Development (246)
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.

Bibliography

Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes & Development, 14(1), 34–44.

Authors 10
  1. Rajani Ravi (first)
  2. Bijoyesh Mookerjee (additional)
  3. Zaver M. Bhujwalla (additional)
  4. Carrie Hayes Sutter (additional)
  5. Dmitri Artemov (additional)
  6. Qinwen Zeng (additional)
  7. Larry E. Dillehay (additional)
  8. Ashima Madan (additional)
  9. Gregg L. Semenza (additional)
  10. Atul Bedi (additional)
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Dates
Type When
Created 3 years, 9 months ago (Nov. 14, 2021, 10:27 p.m.)
Deposited 3 years, 9 months ago (Nov. 14, 2021, 10:29 p.m.)
Indexed 2 weeks, 1 day ago (Aug. 7, 2025, 4:53 p.m.)
Issued 25 years, 7 months ago (Jan. 1, 2000)
Published 25 years, 7 months ago (Jan. 1, 2000)
Published Online 25 years, 7 months ago (Jan. 1, 2000)
Published Print 25 years, 7 months ago (Jan. 1, 2000)
Funders 0

None

@article{Ravi_2000, title={Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α}, volume={14}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.14.1.34}, DOI={10.1101/gad.14.1.34}, number={1}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Ravi, Rajani and Mookerjee, Bijoyesh and Bhujwalla, Zaver M. and Sutter, Carrie Hayes and Artemov, Dmitri and Zeng, Qinwen and Dillehay, Larry E. and Madan, Ashima and Semenza, Gregg L. and Bedi, Atul}, year={2000}, month=jan, pages={34–44} }