Abstract
Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein/coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR- and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / metabolism
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DNA-Binding Proteins / metabolism*
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Disease Models, Animal
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Drug Resistance
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Estrogen Antagonists / pharmacology*
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Gene Expression Regulation
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Genes, Reporter
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Humans
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Mice
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Models, Biological
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Nuclear Proteins / metabolism*
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Protein Binding
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Protein Kinases / metabolism
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Receptors, Estrogen / metabolism*
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Receptors, Retinoic Acid / metabolism
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Repressor Proteins / metabolism*
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Signal Transduction
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Tamoxifen / pharmacology*
Substances
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DNA-Binding Proteins
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Estrogen Antagonists
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NCOR1 protein, human
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NCOR2 protein, human
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Ncor1 protein, mouse
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Ncor2 protein, mouse
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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Receptors, Estrogen
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Receptors, Retinoic Acid
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Repressor Proteins
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Tamoxifen
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Protein Kinases