Coactivators

Muliprotein complexes that do not directly bind DNA, but are recruited by sequence-specific transcription factors and mediate their capacity to activate genes (coactivators) and to repress genes (corepressors). 

Another example is a recently discovered second mode of action by which nuclear receptors modulate transcription. In contrast to DNA-binding-dependent mechanisms, cross talk refers here to gene regulation by protein-protein-interaction of nuclear receptors with other transcription factors, such as AP-1 or NF-kB. Consequently, the nuclear receptor acts as a corepressor or coactivator of transcription. 

The other important molecular target of ethanol is the N-methyl-D-apartate receptor (NMDA-R), which is acutely inhibited although the mechanism is not clear. It was speculated that at least in some brain region the coactivating glycine sites are involved and/or the coactivating polyamine sites. The receptors containing... 

Cytokines such as TNFa and IL-1 3, acting via NF-kB, can induce histone acetylation in both a time- and concentration-dependent manner. Upon DNA binding, NF-kB recruits transcriptional coactivators such as CREB binding protein (CBP) and p300/CBP-associated factor (PCAF). 

An enzyme activity ascribed to many coactivators, which transfers acetyl groups to lysine residues of histone tails of the nucleosomes and thereby facilitate their disruption and the opening of the chromatin. 

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

In the case of liganded NRs, ligand binding is the first and ciucial molecular event that switches the function of these transcription factors from inactive to active state by inducing a conformational change in the LBD of the receptor (Fig. 1). This specific conformation allows the second step of NR activation that corresponds to the recruitment of coregulatoiy complexes, which contain chromatin-modifying enzymes required for transcription. The transcriptional coactivators are very diverse and have expanded to more than hundred in number. These include the pi 60 family of proteins,... 

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... 

Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

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