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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 34-44 |
| Number of pages | 11 |
| Journal | Genes & development |
| Volume | 14 |
| Issue number | 1 |
| State | Published - Jan 1 2000 |
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Keywords
- Angiogenesis
- Cancer
- Hypoxia
- Hypoxia-inducible factor-1 (HIF-1)
- p53
- Vascular endothelial growth factor (VEGF)
ASJC Scopus subject areas
- Genetics
- Developmental Biology
Cite this
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia- inducible factor 1α. / Ravi, Rajani; Mookerjee, Bijoyesh; Bhujwalla, Zaver M; Sutter, Carrie Hayes; Artemov, Dmitri; Zeng, Qinwen; Dillehay, Larry E.; Madan, Ashima; Semenza, Gregg L; Bedi, Atul.
In: Genes & development, Vol. 14, No. 1, 01.01.2000, p. 34-44.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of tumor angiogenesis by p53-induced degradation of hypoxia- inducible factor 1α
AU - Ravi, Rajani
AU - Mookerjee, Bijoyesh
AU - Bhujwalla, Zaver M
AU - Sutter, Carrie Hayes
AU - Artemov, Dmitri
AU - Zeng, Qinwen
AU - Dillehay, Larry E.
AU - Madan, Ashima
AU - Semenza, Gregg L
AU - Bedi, Atul
PY - 2000/1/1
Y1 - 2000/1/1
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Cancer
KW - Hypoxia
KW - Hypoxia-inducible factor-1 (HIF-1)
KW - p53
KW - Vascular endothelial growth factor (VEGF)
UR - http://www.scopus.com/inward/record.url?scp=0033954247&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033954247&partnerID=8YFLogxK
M3 - Article
C2 - 10640274
AN - SCOPUS:0033954247
VL - 14
SP - 34
EP - 44
JO - Genes and Development
JF - Genes and Development
SN - 0890-9369
IS - 1
ER -