Activating signal cointegrator 2 required for liver lipid metabolism mediated by liver X receptors in mice.
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.
Kim
Seung-Whan
SW
Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, Korea.
Park
Keunhee
K
Kwak
Eunyee
E
Choi
Eunho
E
Lee
Seunghee
S
Ham
Jungyeob
J
Kang
Heonjoong
H
Kim
Jong Man
JM
Hwang
Seung Yong
SY
Kong
Young-Yun
YY
Lee
Keesook
K
Lee
Jae Woon
JW
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D056918:Nuclear Receptor Coactivators; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques
D002843:Chromatin; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; C486559:NCOA6 protein, human; C000605213:NR1H3 protein, human; C405683:Ncoa6 protein, mouse; C000605214:Nr1h3 protein, mouse; D056918:Nuclear Receptor Coactivators; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D002784:Cholesterol; D008156:Luciferases; D005982:Glutathione Transferase