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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2003-11-4
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pubmed:abstractText |
Insulin receptor substrate (IRS)-1 and IRS-2 are the major substrates that mediate insulin action. Insulin itself regulates the expression of the IRS protein in the liver, but the underlying mechanisms of IRS-1 and IRS-2 regulation are not fully understood. Here we report that insulin suppressed the expression of both IRS-1 and IRS-2 proteins in Fao hepatoma cells. The decrease in IRS-1 protein occurred via proteasomal degradation without any change in IRS-1 mRNA, whereas the insulin-induced suppression of IRS-2 protein was associated with a parallel decrease in IRS-2 mRNA without changing IRS-2 mRNA half-life. The insulin-induced suppression of IRS-2 mRNA and protein was blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, LY294002, but not by the MAP kinase-ERK kinase (MEK) inhibitor, PD098059. Inhibition of Akt by overexpression of dominant-negative Akt also caused complete attenuation of the insulin-induced decrease in IRS-2 protein and partial attenuation of its mRNA down-regulation. Some nuclear proteins bound to the insulin response element (IRE) sequence on the IRS-2 gene in an insulin-dependent manner in vitro, and the binding was also blocked by the PI 3-kinase inhibitor. Reporter gene assay showed that insulin suppressed the activity of both human and rat IRS-2 gene promoters through the IRE in a PI 3-kinase-dependent manner. Our results indicate that insulin regulates IRS-1 and IRS-2 through different mechanisms and that insulin represses IRS-2 gene expression via a PI 3-kinase/Akt pathway.
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pubmed:language |
eng
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pubmed:journal |
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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/AKT1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Akt1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Chromones,
http://linkedlifedata.com/resource/pubmed/chemical/Cycloheximide,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/IRS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/IRS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Irs1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Irs2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Irs2 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/PD 98059,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Synthesis Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-0795
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
179
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
253-66
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:14596677-Animals,
pubmed-meshheading:14596677-Carcinoma, Hepatocellular,
pubmed-meshheading:14596677-Cell Line,
pubmed-meshheading:14596677-Chromones,
pubmed-meshheading:14596677-Cycloheximide,
pubmed-meshheading:14596677-Depression, Chemical,
pubmed-meshheading:14596677-Enzyme Inhibitors,
pubmed-meshheading:14596677-Flavonoids,
pubmed-meshheading:14596677-Humans,
pubmed-meshheading:14596677-Insulin,
pubmed-meshheading:14596677-Insulin Receptor Substrate Proteins,
pubmed-meshheading:14596677-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:14596677-Liver,
pubmed-meshheading:14596677-Mice,
pubmed-meshheading:14596677-Morpholines,
pubmed-meshheading:14596677-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:14596677-Phosphoproteins,
pubmed-meshheading:14596677-Promoter Regions, Genetic,
pubmed-meshheading:14596677-Protein Synthesis Inhibitors,
pubmed-meshheading:14596677-Protein-Serine-Threonine Kinases,
pubmed-meshheading:14596677-Proto-Oncogene Proteins,
pubmed-meshheading:14596677-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:14596677-RNA, Messenger,
pubmed-meshheading:14596677-Rats,
pubmed-meshheading:14596677-Sequence Alignment,
pubmed-meshheading:14596677-Signal Transduction
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pubmed:year |
2003
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pubmed:articleTitle |
Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase/Akt pathway.
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pubmed:affiliation |
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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