Source:http://linkedlifedata.com/resource/pubmed/id/15082710
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
26
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| pubmed:dateCreated |
2004-6-21
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| pubmed:abstractText |
Interferon-gamma (IFN-gamma) exerts an pleiotropic effect in mesangial cells in inflammatory glomerular diseases. The biologic effect of IFN-gamma is mediated by STAT1alpha. The precise mechanism by which IFN-gamma stimulates the transcriptional activity of STAT1alpha is poorly understood. I investigated the role of protein kinase C (PKC) epsilon in regulating the transcriptional activation of STAT1alpha in mesangial cells. IFN-gamma increased PKCepsilon activity in a time-dependent manner with a concomitant increase in STAT1alpha transcriptional activity. Expression of constitutively active PKCepsilon mimicked the effect of IFN-gamma on STAT1alpha-dependent transcription. Expression of dominant negative PKCepsilon inhibited IFN-gamma-induced STAT1alpha-dependent transcription. Ly294002, a pharmacological inhibitor of phosphatidylinositol (PI) 3-kinase, blocked IFN-gamma-induced PKCepsilon activity and resulted in inhibition of STAT1alpha transcriptional activity but had no effect on STAT1alpha tyrosine phosphorylation and STAT1alpha-DNA complex formation. A PKC inhibitor, H7, also had no effect on STAT1alpha tyrosine phosphorylation and DNA binding. However, Ly294002 and H7 blocked IFN-gamma-induced serine phosphorylation of STAT1alpha. These data indicate that PI 3 kinase-dependent PKCepsilon regulates STAT1alpha transcriptional activity in the absence of any effect on its DNA binding capability. In addition to activating PKCepsilon, IFN-gamma increased MAPK activity, resulting in transcriptional activation of Elk-1, a nuclear target of MAPK. Ly294002 or a dominant negative PI 3-kinase significantly blocked IFN-gamma-induced MAPK activity. On the other hand, ectopic expression of constitutively active PKCepsilon significantly increased MAPK activity. IFN-gamma-stimulated MAPK phosphorylated STAT1alpha in vitro. Inhibition of MAPK activity blocked IFN-gamma-induced serine phosphorylation of STAT1alpha; but its tyrosine phosphorylation and DNA binding were partially inhibited. Finally, expression of dominant negative MAPK significantly inhibited IFN-gamma-induced STAT1alpha-dependent transcription. These data provide the first evidence that IFN-gamma stimulates PKCepsilon in a PI 3-kinase-sensitive manner to activate MAPK, which regulates STAT1alpha transcriptional activity.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-(4-morpholinyl)-8-phenyl-4H-1-benz...,
http://linkedlifedata.com/resource/pubmed/chemical/Chromones,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-Stimulated Gene Factor 3,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Prkce protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C-epsilon,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/gamma interferon activation factor
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
0021-9258
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
25
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| pubmed:volume |
279
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
27399-409
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:15082710-Animals,
pubmed-meshheading:15082710-Cells, Cultured,
pubmed-meshheading:15082710-Chromones,
pubmed-meshheading:15082710-DNA-Binding Proteins,
pubmed-meshheading:15082710-Enzyme Inhibitors,
pubmed-meshheading:15082710-Genes, Reporter,
pubmed-meshheading:15082710-Glomerular Mesangium,
pubmed-meshheading:15082710-Interferon-Stimulated Gene Factor 3,
pubmed-meshheading:15082710-Interferon-gamma,
pubmed-meshheading:15082710-MAP Kinase Signaling System,
pubmed-meshheading:15082710-Mitogen-Activated Protein Kinases,
pubmed-meshheading:15082710-Morpholines,
pubmed-meshheading:15082710-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:15082710-Phosphorylation,
pubmed-meshheading:15082710-Protein Kinase C,
pubmed-meshheading:15082710-Protein Kinase C-epsilon,
pubmed-meshheading:15082710-Rats,
pubmed-meshheading:15082710-Recombinant Proteins,
pubmed-meshheading:15082710-Serine,
pubmed-meshheading:15082710-Transcription Factors,
pubmed-meshheading:15082710-Transcriptional Activation
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| pubmed:year |
2004
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| pubmed:articleTitle |
A linear signal transduction pathway involving phosphatidylinositol 3-kinase, protein kinase Cepsilon, and MAPK in mesangial cells regulates interferon-gamma-induced STAT1alpha transcriptional activation.
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| pubmed:affiliation |
Department of Medicine, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
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