Involvement of p70 S6 kinase in bone morphogenetic protein signaling: vascular endothelial growth factor synthesis by bone morphogenetic protein-4 in osteoblasts.
In the present study, we investigated the effect of bone morphogenetic protein (BMP)-4 on the synthesis of vascular endothelial growth factor (VEGF) in osteoblast-like MC3T3-E1 cells. BMP-4 significantly stimulated VEGF synthesis time-dependently up to 48 h. The stimulatory effect was dose-dependent in the range between 1 and 100 ng/ml. BMP-4 time-dependently phosphorylated p70 S6 kinase. Rapamycin, an inhibitor of p70 S6 kinase, suppressed the BMP-4-stimulated VEGF synthesis as well as the phosphorylation of p70 S6 kinase. The VEGF synthesis by BMP-4 was suppressed by wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase. Both wortmannin and LY294002 inhibited the BMP-4-stimulated phosphorylation of p70 S6 kinase. BMP-4 did not affect the phosphorylation of Akt/protein kinase B. Taken together, our results strongly suggest that p70 S6 kinase takes part in BMP-4-stimulated VEGF synthesis as a positive regulator in osteoblasts and that phosphatidylinositol 3-kinase acts at a point upstream from p70 S6 kinase.
Department of Pharmacology, Gifu University School of Medicine, Gifu 500-8705, Japan.
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Kozawa
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Matsuno
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Uematsu
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008222:Lymphokines / Q000096:biosynthesis*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077191:Wortmannin
D000730:Androstadienes; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002867:Chromones; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D009025:Morpholines; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D000077191:Wortmannin