Coactivator and Corepressors

The transcriptional activity of NRs is also modulated by various posttranslational modifications of the receptors themselves or of their coregulatory proteins. Phosphorylation, as well as several other types of modification, such as acetylation, SUMOylation, ubiquitinylation, and methylation, has been reported to modulate the functions of NRs, potentially constituting an important cellular integration mechanism. In addition to the modifications of the receptors themselves, such modifications have been reported for their coactivators and corepressors. Therefore, these different modes of regulation reveal an unexpected complexity of the dynamics of NR-mediated transcription. 

The multiprotein unit that synthesize RNA by copying the sequence information from the leading strand of the DNA. Its activity is tightly controlled by phosphorylation of the C-termal domain (CTD), access to DNA and interaction by general and sequence specific transcription factors and coactivators and corepressors. 

The understanding of diversity in ligand-mediated ER activity was advanced by the discovery of transcriptional cofactors. These proteins, termed coactivators and corepressors, bind the liganded ER and enhance... 

Target cells have different collections of coactivators and corepressors that... 

Smith CL, Nawaz Z, O Malley BW (1997) Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 11 657... 

Fig. 3.2. Potential genomic and nongenomic activation routes thatmaybe induced by natural or synthetic ER ligands. The hypotheses that explain the tissue-selective action of SERMs include (a) selective activation of ER subtypes, (b) different changes in the 3D configuration of the ligand-ER complex, (c) recruitment of coactivator and corepressor proteins, and (d) activation of alternative response elements in certain inducible genes...

The interaction of glucocorticoid receptors with GREs or other transcription factors is facilitated or inhibited by several families of proteins called steroid receptor coregulators, divided into coactivators and corepressors. The coregulators do this by serving as bridges between the receptors and other nuclear proteins and by expressing enzymatic activities such as histone acetylase or deacetylase, which alter the... 

Fig. 8. Schematic representation of the ligand-induced changes in the confirmation of ER that lead to activities ranging from pure estrogenic (A) to pure antiestrogenic (D) effects. In addition to the ligand-induced changes in the three-dimensional structure of ER, the multiple interactions with cell-specific coactivators and corepressors determine the final activity of each ER-ligand complex in each cell type.

When bound to a response element, the vitamin A-dependent nuclear receptors are able to interact with coactivators and corepressors present in the nucleus either to stimulate or to repress transcriptional activity. Interactions with coactivators or corepressors will result respectively in transcriptional activation or repression. Thus, retinoic acid availability as a ligand for binding to RARs and/or RXRs and the ability of these receptors to bind alternatively to either coactivators or corepressors provides a mechanism through which genes can be either activated or repressed by retinoic acid. It is this gene regulatory mechanism that accounts for the great majority of vitamin A action in the body. 

AF2 and thus shifting the equilibrium between coactivator and corepressor binding (Fig. 2b) (57). However, many nuclear receptors, especially orphan receptors, are constitutively active in the apparent absence of a ligand. Moreover, stmctural studies point to seemingly small receptor-specific differences within the LBDs that must underlie the diversity of receptor action in controlling distinct biologic processes (47). 

Song LN, Coghlan M, Gelmann EP. Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor. Mol. Endocrinol. 2004 18 70-85. 

Nuclear Hormone Receptors Regulate Transcription by Recruiting Coactivators and Corepressors to the Transcription Complex... 

We have seen that nuclear receptors respond to signal molecules by recruiting coactivators and corepressors to the chromatin. Now we can ask. How do coactivators and corepressors modulate transcriptional activity Much of their effectiveness appears to result from their ability to covalently modify the amino-terminal tails of histones and perhaps other proteins. Some of the pl60 coactivators and, in addition, the proteins that they recruit catalyze the transfer of acetyl groups from acetyl CoA to specific lysine residues in the amino-terminal tails of histones. 

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