Abstract
This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. The sequences of human insig-1 and -2 are 59% identical. Both proteins are predicted to contain six transmembrane helices. The proteins differ functionally in two respects: (i) production of insig-1, but not insig-2, in cultured mammalian cells requires nuclear SREBPs; and (ii) at high levels of expression, insig-1, but not insig-2, can block SCAP movement in the absence of exogenous sterols. The combined actions of insig-1 and -2 permit feedback regulation of cholesterol synthesis over a wide range of sterol concentrations.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Blotting, Northern
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CCAAT-Enhancer-Binding Proteins / metabolism*
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CHO Cells
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Carrier Proteins / chemistry*
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Carrier Proteins / physiology*
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Cells, Cultured
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Cholesterol / metabolism
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Cricetinae
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DNA, Complementary / metabolism
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DNA-Binding Proteins / metabolism*
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Dose-Response Relationship, Drug
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Endoplasmic Reticulum / metabolism*
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Golgi Apparatus / metabolism
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Humans
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Immunoblotting
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Intracellular Signaling Peptides and Proteins*
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Membrane Proteins / chemistry*
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Membrane Proteins / metabolism*
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Membrane Proteins / physiology*
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Mice
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Molecular Sequence Data
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Mutation
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Plasmids / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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Proteins / metabolism*
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Proteins / physiology*
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Sequence Homology, Amino Acid
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Sterol Regulatory Element Binding Protein 1
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Time Factors
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Transcription Factors*
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Transfection
Substances
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CCAAT-Enhancer-Binding Proteins
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Carrier Proteins
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DNA, Complementary
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DNA-Binding Proteins
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INSIG2 protein, human
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Proteins
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SREBF1 protein, human
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SREBP cleavage-activating protein
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Srebf1 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Transcription Factors
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Cholesterol
Associated data
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GENBANK/AF527626
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GENBANK/AF527627
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GENBANK/AF527628
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GENBANK/AF527629
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GENBANK/AF527630
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GENBANK/AF527631
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GENBANK/AF527632
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GENBANK/AY112745