Abstract
Activating signal cointegrator 2 (ASC-2), a cancer-amplified transcriptional coactivator of nuclear receptors and many other transcription factors, contains two LXXLL-type nuclear receptor interaction domains. Interestingly, the second LXXLL motif is highly specific to the liver X receptors (LXRs). In cotransfection, DN2, an ASC-2 fragment encompassing this motif, exerts a potent dominant-negative effect on transactivation by LXRs, which is rescued by ectopic coexpression of the full-length ASC-2 but not by other LXXLL-type coactivators, such as SRC-1 and TRAP220. In contrast, DN2/m, in which the LXXLL motif is mutated to LXXAA to abolish the interactions with LXRs, is without any effect. Accordingly, expression of DN2, but not DN2/m, in transgenic mice results in phenotypes that are highly homologous to those previously observed with LXRalpha(-/-) mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXRalpha in the liver upon being fed a high-cholesterol diet. These results identify ASC-2 as a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Cholesterol / metabolism
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Chromatin / metabolism
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DNA, Complementary / metabolism
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DNA-Binding Proteins
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Genes, Dominant
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Glutathione Transferase / metabolism
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Humans
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Immunohistochemistry
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Intracellular Signaling Peptides and Proteins*
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Lipid Metabolism*
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Liver / metabolism*
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Liver X Receptors
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Luciferases / metabolism
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Nuclear Receptor Coactivators
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Oligonucleotide Array Sequence Analysis
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Orphan Nuclear Receptors
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Phenotype
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Precipitin Tests
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Protein Structure, Tertiary
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Amino Acid
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transfection
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Two-Hybrid System Techniques
Substances
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Chromatin
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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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Liver X Receptors
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NCOA6 protein, human
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NR1H3 protein, human
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Ncoa6 protein, mouse
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Nr1h3 protein, mouse
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Nuclear Receptor Coactivators
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Recombinant Fusion Proteins
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Transcription Factors
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Cholesterol
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Luciferases
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Glutathione Transferase