Tags

Type your tag names separated by a space and hit enter

Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway.
Cancer Res. 2001 Oct 01; 61(19):7349-55.CR

Abstract

Many oncogenes induce expression of vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis. Phosphatidylinositol 3'-kinase (PI3K)/Akt is a common signaling pathway for oncogenes and tumor suppressor genes and is involved in VEGF regulation. Because hypoxia is a major stimulus for VEGF production, we examined the effects of LY294002, a selective PI3K inhibitor, on hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression and on endogenous VEGF responses to hypoxia. A panel of breast cancer cell lines reflecting the different genetic changes occurring in human breast cancer was analyzed. LY294002 inhibited HIF-1alpha induction and phosphorylation under hypoxia. However, HIF-2alpha expression was not affected. Basal and hypoxia-inducible VEGF expression was reduced at both mRNA and protein levels by 50%. V12-ras overexpression resulted in an increase in hypoxia-induced HIF-1alpha and HIF-2alpha expression. This effect was blocked by PI3K inhibitor, demonstrating one mechanism for ras synergy with hypoxia-mediated induction of genes. The decreased HIF-1alpha expression was not dependent on VHL interaction because a renal carcinoma cell line with VHL mutation and constitutive high HIF-1alpha expression also showed down-regulation of HIF-1alpha after treatment with LY294002. These results have implications for the use of PI3K inhibitors to inhibit synergistic effects of hypoxia with a wide range of common oncogenes.

Authors+Show Affiliations

Imperial Cancer Research Fund, Molecular Oncology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11585776

Citation

Blancher, C, et al. "Effects of Ras and Von Hippel-Lindau (VHL) Gene Mutations On Hypoxia-inducible Factor (HIF)-1alpha, HIF-2alpha, and Vascular Endothelial Growth Factor Expression and Their Regulation By the Phosphatidylinositol 3'-kinase/Akt Signaling Pathway." Cancer Research, vol. 61, no. 19, 2001, pp. 7349-55.
Blancher C, Moore JW, Robertson N, et al. Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer Res. 2001;61(19):7349-55.
Blancher, C., Moore, J. W., Robertson, N., & Harris, A. L. (2001). Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. Cancer Research, 61(19), 7349-55.
Blancher C, et al. Effects of Ras and Von Hippel-Lindau (VHL) Gene Mutations On Hypoxia-inducible Factor (HIF)-1alpha, HIF-2alpha, and Vascular Endothelial Growth Factor Expression and Their Regulation By the Phosphatidylinositol 3'-kinase/Akt Signaling Pathway. Cancer Res. 2001 Oct 1;61(19):7349-55. PubMed PMID: 11585776.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway. AU - Blancher,C, AU - Moore,J W, AU - Robertson,N, AU - Harris,A L, PY - 2001/10/5/pubmed PY - 2001/10/19/medline PY - 2001/10/5/entrez SP - 7349 EP - 55 JF - Cancer research JO - Cancer Res VL - 61 IS - 19 N2 - Many oncogenes induce expression of vascular endothelial growth factor (VEGF), a key factor in tumor angiogenesis. Phosphatidylinositol 3'-kinase (PI3K)/Akt is a common signaling pathway for oncogenes and tumor suppressor genes and is involved in VEGF regulation. Because hypoxia is a major stimulus for VEGF production, we examined the effects of LY294002, a selective PI3K inhibitor, on hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression and on endogenous VEGF responses to hypoxia. A panel of breast cancer cell lines reflecting the different genetic changes occurring in human breast cancer was analyzed. LY294002 inhibited HIF-1alpha induction and phosphorylation under hypoxia. However, HIF-2alpha expression was not affected. Basal and hypoxia-inducible VEGF expression was reduced at both mRNA and protein levels by 50%. V12-ras overexpression resulted in an increase in hypoxia-induced HIF-1alpha and HIF-2alpha expression. This effect was blocked by PI3K inhibitor, demonstrating one mechanism for ras synergy with hypoxia-mediated induction of genes. The decreased HIF-1alpha expression was not dependent on VHL interaction because a renal carcinoma cell line with VHL mutation and constitutive high HIF-1alpha expression also showed down-regulation of HIF-1alpha after treatment with LY294002. These results have implications for the use of PI3K inhibitors to inhibit synergistic effects of hypoxia with a wide range of common oncogenes. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11585776/Effects_of_ras_and_von_Hippel_Lindau__VHL__gene_mutations_on_hypoxia_inducible_factor__HIF__1alpha_HIF_2alpha_and_vascular_endothelial_growth_factor_expression_and_their_regulation_by_the_phosphatidylinositol_3'_kinase/Akt_signaling_pathway_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11585776 DB - PRIME DP - Unbound Medicine ER -