Abstract
Nuclear retinoic acid (RA) receptors (RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. Here we show that during RA-dependent activation of the RARalpha isotype, the p160 coactivator pCIP/ACTR/AIB-1/RAC-3/TRAM-1/SRC-3 is phosphorylated by p38MAPK. SRC-3 phosphorylation has been correlated to an initial facilitation of RARalpha-target genes activation, via the control of the dynamics of the interactions of the coactivator with RARalpha. Then, phosphorylation inhibits transcription via promoting the degradation of SRC-3. In line with this, inhibition of p38MAPK markedly enhances RARalpha-mediated transcription and RA-dependent induction of cell differentiation. SRC-3 phosphorylation and degradation occur only within the context of RARalpha complexes, suggesting that the RAR isotype defines a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We propose a model in which RARalpha transcriptional activity is regulated by SRC-3 through coordinated events that are fine-tuned by RA and p38MAPK.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyltransferases / metabolism*
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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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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HL-60 Cells
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Histone Acetyltransferases
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Humans
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Mice
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Multiprotein Complexes / metabolism
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Nuclear Receptor Coactivator 3
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Oncogene Proteins / metabolism*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Protein Processing, Post-Translational / physiology*
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Receptors, Retinoic Acid / metabolism*
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Retinoic Acid Receptor alpha
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Trans-Activators / metabolism*
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology*
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Tretinoin / metabolism
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Tretinoin / pharmacology
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antineoplastic Agents
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Multiprotein Complexes
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Oncogene Proteins
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RARA protein, human
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Rara protein, mouse
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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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Tretinoin
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Acetyltransferases
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Histone Acetyltransferases
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NCOA3 protein, human
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Ncoa3 protein, mouse
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Nuclear Receptor Coactivator 3
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p38 Mitogen-Activated Protein Kinases