Transcription coactivators

Mediators and coactivators. Transcriptional activators that act in a crude cell-free system often do not function with purified DNA, RNA polymerase, and the basal transcription factors as indicated in Eq. 28-5. Studies with yeast, Drosophila, and human cells revealed that additional large multisubunit complexes known as mediators are needed 272/346-348 A yeast mediator complex consists of 20 subunits.349-350b Many activator proteins bind to the DNA sequences known as enchancers, discussed in the next section. Mediator complexes may also interact with enhancer-bound activators. Individual proteins, such as the TAF subunits, that bind to and cooperate with activator proteins are often called coactivators.351... 

Mediators and coactivators. Transcriptional activators that act in a crude cell-free system often do not function with purified DNA, RNA polymerase, and the basal transcription factors as indicated in Eq. 

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. 

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). 

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. 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

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