Abstract
We have identified a new retinoid response pathway through which 9-cis retinoic acid (9cRA) activates transcription in the presence of LXR alpha, a member of the nuclear receptor superfamily. LXR alpha shows a specific pattern of expression in visceral organs, thereby restricting the response to certain tissues. Retinoid trans-activation occurs selectively on a distinct response element termed an LXRE. Significantly, neither RXR homodimers nor RXR/RAR heterodimers are able to substitute for LXR alpha in mediating this retinoid response. We provide evidence that the retinoid response on the LXRE is the result of a unique interaction between LXR alpha and endogenous RXR, which, unlike in the RXR/RAR heterodimer, makes RXR competent to respond to retinoids. Thus, the interaction with LXR alpha shifts RXR from its role described previously as a silent, DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXREs.
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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Base Sequence
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Binding Sites
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Cloning, Molecular
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DNA / metabolism
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DNA-Binding Proteins
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Gene Expression Regulation, Developmental
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Humans
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Ligands
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Liver X Receptors
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Mice
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Molecular Sequence Data
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Nuclear Proteins / metabolism*
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Organ Specificity
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Orphan Nuclear Receptors
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Promoter Regions, Genetic / genetics
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RNA, Messenger / analysis
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Rats
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / genetics*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Retinoic Acid / metabolism*
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Repetitive Sequences, Nucleic Acid / genetics
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Retinoid X Receptors
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Sequence Analysis, DNA
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Signal Transduction / physiology
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Transcription Factors / metabolism*
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Transcriptional Activation / physiology*
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Tretinoin / metabolism
Substances
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DNA-Binding Proteins
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Ligands
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Liver X Receptors
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NR1H3 protein, human
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Nr1h3 protein, mouse
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Nr1h3 protein, rat
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Nuclear Proteins
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Orphan Nuclear Receptors
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Transcription Factors
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Tretinoin
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DNA