Abstract
Nuclear retinoic acid receptor alpha (RARalpha) activates gene expression through dynamic interactions with coregulatory protein complexes, the assembly of which is directed by the ligand and the AF-2 domain of RARalpha. Then RARalpha and its coactivator SRC-3 are degraded by the proteasome. Recently it has emerged that the proteasome also plays a key role in RARalpha-mediated transcription. Here we show that SUG-1, one of the six ATPases of the 19 S regulatory complex of the 26 S proteasome, interacts with SRC-3, is recruited at the promoters of retinoic acid (RA) target genes, and thereby participates to their transcription. In addition, SUG-1 also mediates the proteasomal degradation of SRC-3. However, when present in excess amounts, SUG-1 blocks the activation of RARalpha target genes and the degradation of RARalpha that occurs in response to RA, via its ability to interfere with the recruitment of SRC-3 and other coregulators at the AF-2 domain of RARalpha. We propose a model in which the ratio between SUG-1 and SRC-3 is crucial for the control of RARalpha functioning. This study provides new insights into how SUG-1 has a unique role in linking the transcription and degradation processes via its ability to interact with SRC-3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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COS Cells
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Chlorocebus aethiops
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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HeLa Cells
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism*
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Humans
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LIM Domain Proteins
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Models, Biological
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Nuclear Receptor Coactivator 3
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Proteasome Endopeptidase Complex / metabolism*
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Protein Structure, Tertiary / physiology
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism*
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Retinoic Acid Receptor alpha
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology
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Tretinoin / pharmacology*
Substances
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Adaptor Proteins, Signal Transducing
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LIM Domain Proteins
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PSMC5 protein, human
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RARA protein, human
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Trans-Activators
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Transcription Factors
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Tretinoin
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Histone Acetyltransferases
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NCOA3 protein, human
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Nuclear Receptor Coactivator 3
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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ATPases Associated with Diverse Cellular Activities