Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2α

Nagako Akeno, Jared Robins, Mei Zhang, Maria F. Czyzyk-Krzeska, Thomas Clemens

Research output: Contribution to journalArticle

Abstract

IGF-I is known to stimulate the expression of oxygen- and nutrient-sensitive genes in several cell types. In this study we investigated the signaling pathways and transcriptional mechanisms that mediate IGF-I induction of vascular endothelial growth factor (VEGF) expression in human osteoblast-like cells. IGF-I (50 ng/ml) induced a rapid increase (3-fold) in VEGF mRNA in osteoblasts that was accompanied by an increase in the level of hypoxia-inducible factor-2α (HIF-2α) protein without changes in HIF-2α mRNA expression. These effects were mimicked by chemical inhibition of proteosomal degradation of HIF-2α. Transcriptional activation of a proximal VEGF promoter-luciferase construct was greatly enhanced by cotransfection with an HIF-2α, but not an HIF-1α, construct. IGF-I acutely stimulated Akt phosphorylation, which was abolished by pretreatment of cells with the PI3K inhibitor LY294002. Pretreatment of the cells with LY294002 also greatly attenuated IGF-I induction of HIF-2α and blunted IGF-I-induced VEGF promoter activity. Finally, forced expression of a constitutively active PI3K expression construct induced VEGF promoter to levels similar to those observed with IGF-I alone. These data indicate that IGF-I, by activation of the PI3K pathway, induces VEGF expression in osteoblasts through a transcriptional control mechanism common to those that activate VEGF and other hypoxia response genes.

Original languageEnglish (US)
Pages (from-to)420-425
Number of pages6
JournalEndocrinology
Volume143
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

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Osteoblasts
Phosphatidylinositol 3-Kinases
Insulin-Like Growth Factor I
Vascular Endothelial Growth Factor A
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Messenger RNA
endothelial PAS domain-containing protein 1
Luciferases
Transcriptional Activation
Genes
Phosphorylation
Oxygen
Food
Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2α. / Akeno, Nagako; Robins, Jared; Zhang, Mei; Czyzyk-Krzeska, Maria F.; Clemens, Thomas.

In: Endocrinology, Vol. 143, No. 2, 2002, p. 420-425.

Research output: Contribution to journalArticle

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