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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
41
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pubmed:dateCreated |
2004-10-6
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pubmed:abstractText |
Insig-1 and Insig-2 are membrane proteins of the endoplasmic reticulum that regulate lipid metabolism by the following two actions: 1) sterol-induced binding to 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an action that leads to ubiquitination and degradation of the enzyme; and 2) sterol-induced binding to SREBP cleavage-activating protein, an action that blocks the proteolytic processing of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that enhance the synthesis of cholesterol and fatty acids. Here we report the isolation of a new mutant line of Chinese hamster ovary cells, designated SRD-14, in which Insig-1 mRNA and protein are not produced due to a partial deletion of the INSIG-1 gene. The SRD-14 cells were produced by gamma-irradiation, followed by selection with the 1,1-bisphosphonate ester SR-12813, which mimics sterols in accelerating reductase degradation but does not block SREBP processing. SRD-14 cells fail to respond to sterols by promoting reductase ubiquitination and degradation. The rate at which sterols suppress SREBP processing is significantly slower in SRD-14 cells than wild type CHO-7 cells. Sterol regulation of reductase degradation and SREBP processing is restored when SRD-14 cells are transfected with expression plasmids encoding either Insig-1 or Insig-2. These results provide formal genetic proof for the essential role of Insig-1 in feedback control of lipid synthesis in cultured cells.
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pubmed:grant |
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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/CCAAT-Enhancer-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Diphosphonates,
http://linkedlifedata.com/resource/pubmed/chemical/Fatty Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxymethylglutaryl CoA Reductases,
http://linkedlifedata.com/resource/pubmed/chemical/INSIG1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/SR 12813,
http://linkedlifedata.com/resource/pubmed/chemical/SREBF1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Sterol Regulatory Element Binding...,
http://linkedlifedata.com/resource/pubmed/chemical/Sterols,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
8
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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 |
43136-47
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:15247248-Animals,
pubmed-meshheading:15247248-CCAAT-Enhancer-Binding Proteins,
pubmed-meshheading:15247248-CHO Cells,
pubmed-meshheading:15247248-Cell Line,
pubmed-meshheading:15247248-Cell Nucleus,
pubmed-meshheading:15247248-Cholesterol,
pubmed-meshheading:15247248-Cricetinae,
pubmed-meshheading:15247248-DNA,
pubmed-meshheading:15247248-DNA-Binding Proteins,
pubmed-meshheading:15247248-Diphosphonates,
pubmed-meshheading:15247248-Dose-Response Relationship, Drug,
pubmed-meshheading:15247248-Endoplasmic Reticulum,
pubmed-meshheading:15247248-Fatty Acids,
pubmed-meshheading:15247248-Fibroblasts,
pubmed-meshheading:15247248-Humans,
pubmed-meshheading:15247248-Hydroxymethylglutaryl CoA Reductases,
pubmed-meshheading:15247248-Immunoblotting,
pubmed-meshheading:15247248-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:15247248-Lipid Metabolism,
pubmed-meshheading:15247248-Membrane Proteins,
pubmed-meshheading:15247248-Models, Biological,
pubmed-meshheading:15247248-Mutagenesis, Site-Directed,
pubmed-meshheading:15247248-Mutation,
pubmed-meshheading:15247248-Peptides,
pubmed-meshheading:15247248-Plasmids,
pubmed-meshheading:15247248-RNA Interference,
pubmed-meshheading:15247248-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:15247248-Sterol Regulatory Element Binding Protein 1,
pubmed-meshheading:15247248-Sterols,
pubmed-meshheading:15247248-Subcellular Fractions,
pubmed-meshheading:15247248-Temperature,
pubmed-meshheading:15247248-Time Factors,
pubmed-meshheading:15247248-Transcription Factors,
pubmed-meshheading:15247248-Transfection,
pubmed-meshheading:15247248-Ubiquitin
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pubmed:year |
2004
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pubmed:articleTitle |
Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
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pubmed:affiliation |
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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