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

By R. Ravi, B. Mookerjee, Z. Bhujwalla, C. H. Sutter, D. Artemov, Qinwen Zeng, L. Dillehay, A. Madan, G. Semenza, A. Bedi. Genes & Development, 2000

1,236 citations recorded by the source corpus.

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-1alpha 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-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha 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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5c0770cda1be256df47794076979768b0350af33

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. G. Semenza
2. Roland H. Wenger
3. P. Ratcliffe
4. Adrian L. Harris
5. S. Påhlman
6. C. Wigerup
7. D. Bexell
8. C. Pugh

In Molecular Biology

1. G. Semenza
2. P. Ratcliffe
3. Roland H. Wenger
4. Adrian L. Harris
5. S. Påhlman
6. C. Wigerup
7. D. Bexell
8. C. Pugh

In Oncology

1. G. Semenza
2. Max Costa
3. Adrian L. Harris
4. Alan R. Fersht
5. Qingdong Ke
6. P. Vaupel

Citations in the corpus

• Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes (2001, background): “The tumor suppressor gene products p53 and VHL have inhibitory effects on angiogenesi”
• Hypoxia-Inducible Factor-1 (HIF-1) (2006, background): “In addition, loss of function of wildtype p53, which is inactivated in most of human cancers, increased HIF-1 levels and enhanced HIF-dependent transcription in tumors (Ravi et al., 2000).”
• Binding of Natively Unfolded HIF-1α ODD Domain to p53 (2005, methodology): “The tween p53 and HIF-1 mediates p53 hypoxic accumulation (An et al., 1998; Hansson et al., 2002; Ravi et al., 2000).”
• HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, neutral): “For example, PTEN or p53 loss of function leads to increased HIF-1 α synthesis and stability, respectively (77–79).”
• Vascular Endothelial Growth Factor and Angiogenesis (2004, background): “…product promotes the expression of inhibitors of angiogenesis, such as thrombospondin, and inhibits the expression of VEGF-A, but not VEGF-B or VEGF-C (Fontanini et al., 1998; Ravi et al., 2000). p53 is mutated in 50% of all cancers and is also inactivated by viral oncoproteins (Yuan et al., 2002).”
• Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. (2016, background): “Intriguingly, p53 can also promote Mdm2-mediated degradation of HIF-1α (Ravi et al., 2000).”