Abstract
Cellular stresses inhibit retinoid signaling, but the molecular basis for this phenomenon has not been revealed. Here, we present evidence that retinoid X receptor (RXR) is a substrate for both mitogen-activated protein kinase kinase-4 (MKK4/SEK1) and its downstream mediator c-Jun N-terminal kinase (JNK). MKK4/SEK1 and JNK recognized distinct features on RXR in the DE and AB regions, respectively. Phosphorylation by MKK4/SEK1 had profound effects on the biochemical properties of RXR, inhibiting the expression of genes activated by RXR-retinoic acid receptor complexes. Tyr-249 in the RXR DE region was required for the inhibitory effect of MKK4/SEK1. These effects were significantly reduced in MKK4/SEK1-null cells, indicating that MKK4/SEK1 is required for the suppression of retinoid signaling by stress. Findings presented here demonstrate that MKK4/SEK1 can directly modulate transcription by phosphorylating RXR, a novel MKK4/SEK1 substrate.
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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Animals
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COS Cells
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Enzyme Activation
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Gene Deletion
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Gene Expression Regulation* / drug effects
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Genes, Reporter / genetics
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JNK Mitogen-Activated Protein Kinases
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Laminin / genetics
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Ligands
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MAP Kinase Kinase 4*
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Mice
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Mutagenesis, Site-Directed
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Phosphorylation
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Receptors, Retinoic Acid / chemistry
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism*
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Retinoid X Receptors
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Signal Transduction / drug effects
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transfection
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Tretinoin / antagonists & inhibitors
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Tretinoin / pharmacology
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Tyrosine / genetics
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Tyrosine / metabolism
Substances
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Laminin
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Ligands
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Transcription Factors
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Tyrosine
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Tretinoin
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Mitogen-Activated Protein Kinase 9
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Map2k4 protein, mouse
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Mitogen-Activated Protein Kinase Kinases