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Gene interactions and pathways from curated databases and text-mining
Mol Cancer Res 2003, PMID: 12612059

Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth factor-I-induced vascular endothelial growth factor synthesis in prostate epithelial cells: a role for hypoxia-inducible factor-1?

Burroughs, Kevin D; Oh, Jennifer; Barrett, J Carl; DiAugustine, Richard P

Due to the importance of vascular endothelial growth factor (VEGF) in the neovascularization of solid tumors, a clear understanding of how VEGF is regulated in normal and tumor cells is warranted. We investigated insulin-like growth factor (IGF)-I-stimulated signaling pathways that increase the rate of VEGF synthesis in primary cultures of normal prostate epithelial cells (PrEC). IGF-I increased the secretion of VEGF(165) into PrEC growth medium and stimulated transcription of a reporter gene driven by a 1.5-kb region of the VEGF promoter. Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling pathways completely abrogated the IGF-I-induced increase in VEGF secretion and promoter activity, indicating a dependence on coordinate signaling from both pathways to produce this effect. Levels of the transcription factors hypoxia-inducible factor (HIF)-1 and Fos were elevated in response to IGF-I in a PI3-K-dependent and Mek1/2-dependent manner, respectively. The expression of an activator protein (AP)-1 dominant negative in an immortalized prostate epithelial cell line PZ-HPV-7 suppressed the IGF-I-induced increase in VEGF promoter activity. Mutation of the hypoxia response element (HRE), which mediates hypoxic stimulation of VEGF transcription, did not inhibit the effect of IGF-I on the VEGF promoter, despite the fact that this mutation inhibited PI3-K-stimulated VEGF promoter activity in prostate cancer cells. These data indicate that PI3-K signaling does not increase VEGF transcription through transactivation by HIF-1 at the HRE in normal PrEC. This work also suggests that an additional signal, not stimulated by IGF-I in PrEC, is needed for HIF-1 to stimulate transcription from the VEGF HRE.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

vascular endothelial growth factor → insulin-like growth factor-I: " Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth factor-I induced vascular endothelial growth factor synthesis in prostate epithelial cells : a role for hypoxia-inducible factor-1 ? "

vascular endothelial growth factor → mek1/2: " Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth factor-I induced vascular endothelial growth factor synthesis in prostate epithelial cells : a role for hypoxia-inducible factor-1 ? "

vascular endothelial growth factor → mek1/2: " Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth factor-I induced vascular endothelial growth factor synthesis in prostate epithelial cells : a role for hypoxia-inducible factor-1 ? "

vascular endothelial growth factor → Phosphatidylinositol 3-kinase: " Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth factor-I induced vascular endothelial growth factor synthesis in prostate epithelial cells : a role for hypoxia-inducible factor-1 ? "

VEGF → IGF-I: " IGF-I increased the secretion of VEGF ( 165 ) into PrEC growth medium and stimulated transcription of a reporter gene driven by a 1.5-kb region of the VEGF promoter "

VEGF → IGF-I: " Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling pathways completely abrogated the IGF-I induced increase in VEGF secretion and promoter activity, indicating a dependence on coordinate signaling from both pathways to produce this effect "

VEGF ⊣ activator protein (AP)-1: " The expression of an activator protein (AP)-1 dominant negative in an immortalized prostate epithelial cell line PZ-HPV-7 suppressed the IGF-I induced increase in VEGF promoter activity "

VEGF → IGF-I: " The expression of an activator protein (AP)-1 dominant negative in an immortalized prostate epithelial cell line PZ-HPV-7 suppressed the IGF-I induced increase in VEGF promoter activity "

VEGF → PI3-K: " Mutation of the hypoxia response element ( HRE ), which mediates hypoxic stimulation of VEGF transcription, did not inhibit the effect of IGF-I on the VEGF promoter, despite the fact that this mutation inhibited PI3-K stimulated VEGF promoter activity in prostate cancer cells "

VEGF — IGF-I: " Mutation of the hypoxia response element ( HRE ), which mediates hypoxic stimulation of VEGF transcription, did not inhibit the effect of IGF-I on the VEGF promoter, despite the fact that this mutation inhibited PI3-K stimulated VEGF promoter activity in prostate cancer cells "

VEGF → PI3-K: " These data indicate that PI3-K signaling does not increase VEGF transcription through transactivation by HIF-1 at the HRE in normal PrEC "

Manually curated Databases

No curated data.