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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Ravi, R. Mookerjee, B. Bhujwalla, Z. M. Sutter, C. H. Artemov, D. Zeng, Q. Dillehay, L. E. Madan, A. Semenza, G. L. Bedi, A. |
| Description | Author Affiliation: Ravi R ( Johns Hopkins Oncology Center, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 USA.) |
| 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-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. |
| File Format | HTM / HTML |
| ISSN | 08909369 |
| e-ISSN | 15495477 |
| Journal | Genes & Development |
| Issue Number | 1 |
| Volume Number | 14 |
| Language | English |
| Publisher | Cold Spring Harbor Laboratory Press |
| Publisher Date | 2000-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Molecular Discipline Biology__semicolon__developmental Discipline Biology__semicolon__genetics__semicolon__cell Discipline Biology Adenocarcinoma Blood Supply Colonic Neoplasms Dna-binding Proteins Metabolism Neovascularization, Pathologic Nuclear Proteins Transcription Factors Tumor Suppressor Protein P53 Physiology Pathology Animals Cell Division Endothelial Growth Factors Genetics Genotype Hydrolysis Hypoxia-inducible Factor 1 Hypoxia-inducible Factor 1, Alpha Subunit Lymphokines Mice Oxygen Tumor Cells, Cultured Ubiquitins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, Non-p.h.s. Research Support, U.s. Gov't, P.h.s. |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Developmental Biology |
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