Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) plays an essential role in the initiation and regulation of angiogenesis-a crucial component of wound healing and cancer growth. Prostaglandins (PGs) stimulate angiogenesis but the precise mechanisms of their pro-angiogenic actions remain unexplained. We investigated whether prostaglandin E(2) (PGE(2)) can induce VEGF expression in rat gastric microvascular endothelial cells (RGMEC) and the signaling pathway(s) involved. We demonstrated that PGE(2) significantly increased ERK2 and JNK1 activation and VEGF mRNA and protein expression. Incubation of RGMEC with PD 98059 (MEK kinase inhibitor) significantly reduced PGE(2)-induced ERK2 activity, VEGF mRNA and protein expression. Furthermore, PD 98059 treatment almost completely abolished JNK1 activation. Our data suggest that PGE(2)-stimulates VEGF expression in RGMEC via transactivation of JNK1 by ERK2. One potential implication of this finding is that increased PG levels in cancers could facilitate tumor growth by stimulating VEGF synthesis and angiogenesis.
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PMID:PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. 1152 87

The effects of insulin on vascular endothelial growth factor (VEGF) expression in cultured vascular cells and in angiogenesis were characterized. Insulin increased VEGF mRNA levels in mouse aortic smooth muscle cells from 10(-9) to 10(-7) m with an initial peak of 3.7-fold increases at 1 h and a second peak of 2.8-fold after 12 h. The first peak of VEGF expression was inhibited by LY294002, an inhibitor of phosphatidylinositol (PI) 3-kinase, and by the overexpression of dominant negative forms of p85 subunit of PI 3-kinase or Akt. Inhibitors of MEK kinase, PD98059, or overexpression of dominant negative forms of Ras was ineffective. In contrast, the chronic effect of insulin on VEGF expression was partially inhibited by both LY294002 or PD98059 as well as by the overexpression of dominant negatives of PI 3-kinase or Ras. The importance of PI 3-kinase-Akt pathway on VEGF expression was confirmed in mouse aortic smooth muscle cells isolated from insulin receptor substrate -1 knockout (IRS-1-/-) mice that showed parallel reductions of 46-49% in insulin-stimulated VEGF expression and PI 3-kinase-Akt activation. Insulin-induced activation of PI 3-kinase-Akt on hypoxia-induced VEGF expression and neovascularization was reduced by 40% in the retina of neonatal hypoxia model using IRS-1-/- mice. Thus, unlike other cells, insulin can regulate VEGF expression by both IRS-1/PI 3-kinase-Akt cascade and Ras-MAPK pathways in aortic smooth muscle cells. The in vivo results provide direct evidence that insulin can modulate hypoxia-induced angiogenesis via reduction in VEGF expression in vivo.
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PMID:Characterization of multiple signaling pathways of insulin in the regulation of vascular endothelial growth factor expression in vascular cells and angiogenesis. 1277 12

Vascular endothelial growth factor (VEGF) plays an essential role in the initiation and regulation of angiogenesis, which is a crucial component of wound healing and vessel growth. Tissue-type plasminogen activator (t-PA) could stimulate angiogenesis but the precise mechanisms of their proangiogenic actions remain unclear. We investigated whether t-PA can induce VEGF expression in ECV304 and further explored the underlying signaling pathway(s) involved. Through adenovirus mediated overexpression of t-PA in ECV304 cells, we demonstrated that t-PA significantly increased both VEGF mRNA and protein expression. A further mechanistic study showed that both ERK and p38 MAPK activation were involved in this process. Incubation of RVEC with PD 98059 (MEK kinase inhibitor) significantly reduced t-PA-induced ERK2 activity, VEGF mRNA and protein expression. Furthermore, PD 98059 treatment almost completely abolished p38 activation. Our data suggest that t-PA-stimulates VEGF expression in RVEC via transactivation of p38 by ERK. One potential implication of this finding is that increased t-PA levels in thomb could facilitate vessel growth by stimulating VEGF synthesis and angiogenesis.
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PMID:t-PA stimulates VEGF expression in endothelial cells via ERK2/p38 signaling pathways. 2460 Dec 28