Abstract
Through expression cloning we have isolated a cDNA-encoding SREBP cleavage-activating protein (SCAP), which regulates cholesterol metabolism by stimulating cleavage of transcription factors SREBP-1 and -2, thereby releasing them from membranes. The cDNA was isolated from Chinese hamster ovary cells with a dominant mutation that renders them resistant to sterol-mediated suppression of cholesterol synthesis and uptake. Sterol resistance was traced to a G-->A transition at codon 443 of SCAP, changing aspartic acid to asparagine. The D443N mutation enhances the cleavage-stimulating ability of SCAP and renders it resistant to inhibition by sterols. SCAP has multiple membrane-spanning regions, five of which resemble the sterol-sensing domain of HMG CoA reductase, an endoplasmic reticulum enzyme whose degradation is accelerated by sterols. SCAP appears to be a central regulator of cholesterol metabolism in animal cells.
Publication types
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Comparative Study
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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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CCAAT-Enhancer-Binding Proteins*
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CHO Cells / drug effects
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CHO Cells / metabolism*
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Caenorhabditis elegans / genetics
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Cholesterol / metabolism*
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Cloning, Molecular
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Cricetinae
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Cricetulus
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DNA, Complementary / genetics
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DNA-Binding Proteins / metabolism*
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Feedback
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Gene Expression Regulation
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Genes*
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Genes, Reporter
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Humans
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Hydroxymethylglutaryl CoA Reductases / chemistry
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Molecular Sequence Data
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Nuclear Proteins / metabolism*
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Receptors, LDL / biosynthesis*
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Receptors, LDL / genetics
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Sequence Alignment
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Sequence Homology, Amino Acid
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Species Specificity
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Sterols / pharmacology*
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Transcription Factors / metabolism
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Transfection
Substances
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CCAAT-Enhancer-Binding Proteins
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DNA, Complementary
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nuclear Proteins
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Receptors, LDL
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SREBF1 protein, human
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SREBF2 protein, human
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SREBP cleavage-activating protein
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Sterols
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Transcription Factors
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Cholesterol
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Hydroxymethylglutaryl CoA Reductases
Associated data
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GENBANK/D83782
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GENBANK/U67060