Linked Life Data

15308628

Source:http://linkedlifedata.com/resource/pubmed/id/15308628

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
42
pubmed:dateCreated
2004-10-11
pubmed:abstractText
The mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) plays a critical cytoprotective role against oxidative stress. Vascular endothelial growth factor (VEGF) was shown previously to induce expression of Mn-SOD in endothelial cells by a NADPH oxidase-dependent mechanism. The goal of the current study was to determine the transcriptional mechanisms underlying this phenomenon. VEGF resulted in protein kinase C-dependent phosphorylation of IkappaB and subsequent translocation of p65 NF-kappaB into the nucleus. Overexpression of constitutively active IkappaB blocked VEGF stimulation of Mn-SOD. In transient transfection assays, VEGF increased Mn-SOD promoter activity, an effect that was dependent on a second intronic NF-kappaB consensus motif. In contrast, VEGF-mediated induction of Mn-SOD was enhanced by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and by dominant negative Akt and was decreased by constitutively active Akt. Overexpression of a constitutively active (phosphorylation-resistant) form of FKHRL1 (TMFKHRL1) resulted in increased Mn-SOD expression, suggesting that the negative effect of PI3K-Akt involves attenuation of forkhead activity. In co-transfection assays, the Mn-SOD promoter was transactivated by TMFKHRL1. Flavoenzyme inhibitor, diphenyleneiodonium (DPI), and antisense oligonucleotides against p47phox (AS-p47phox) inhibited VEGF stimulation of IkappaB/NF-kappaB and forkhead phosphorylation, supporting a role for NADPH oxidase activity in both signaling pathways. Like VEGF, hepatocyte growth factor (HGF) activated the PI3K-Akt-forkhead pathway. However, HGF-PI3K-Akt-forkhead signaling was insensitive to diphenyleneiodonium and AS-p47phox. Moreover, HGF failed to induce phosphorylation of IkappaB/NF-kappaB or nuclear translocation of NF-kappaB and had no effect on Mn-SOD expression. Together, these data suggest that VEGF is uniquely coupled to Mn-SOD expression through growth factor-specific reactive oxygen species (ROS)-sensitive positive (protein kinase C-NF-kappaB) and negative (PI3K-Akt-forkhead) signaling pathways.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
44030-8
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:15308628-Active Transport, Cell Nucleus, pubmed-meshheading:15308628-Cell Line, pubmed-meshheading:15308628-Cells, Cultured, pubmed-meshheading:15308628-Coronary Vessels, pubmed-meshheading:15308628-Endothelium, Vascular, pubmed-meshheading:15308628-Enzyme Induction, pubmed-meshheading:15308628-Forkhead Transcription Factors, pubmed-meshheading:15308628-Humans, pubmed-meshheading:15308628-I-kappa B Proteins, pubmed-meshheading:15308628-NADPH Oxidase, pubmed-meshheading:15308628-NF-kappa B, pubmed-meshheading:15308628-Nuclear Proteins, pubmed-meshheading:15308628-Oxidation-Reduction, pubmed-meshheading:15308628-Oxidative Stress, pubmed-meshheading:15308628-Phosphorylation, pubmed-meshheading:15308628-Superoxide Dismutase, pubmed-meshheading:15308628-Transcription Factors, pubmed-meshheading:15308628-Umbilical Veins
pubmed:year
2004
pubmed:articleTitle
Vascular endothelial growth factor-mediated induction of manganese superoxide dismutase occurs through redox-dependent regulation of forkhead and IkappaB/NF-kappaB.
pubmed:affiliation
Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. rabid@bidmc.harvard.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't