Transactivating domain Phosphorylation

The JNK/SAPK proteins bind to the N-terminal transactivation domain of c-Jun protein and phosphorylate the residues Ser63 and Ser73. Consequently, increased transcription activity is observed of genes controlled by c-Jim. 

The transcription factors regulated by the JNK/SAPK and p38 proteins include the Elkl, ATF2, and c-Jun proteins. As expressed by their name, the c-Jun terminal protein kinases phosphorylate the c-Jun protein at residues Ser63 and Ser73. These phosphorylation sites are located within the transactivation domain of c-Jun, and their phosphorylation correlates with enhanced trans-activating activity. 

Substrate recognition and selection of the JNK/SAPK and p38 proteins (and also the ERK proteins) are mediated both by specific docking sites and by the nature of the amino acids surrounding the phosphoacceptor site. For the transcription factor substrates, specific docking domains have been identified that are loacted at a distance from the phosphorylation sites in the transactivation domain. These docking sites serve to increase the selectivity and specificity of phosphorylation, and they are used for recruitment of MAPK kinases into protein complexes at promotors, where they can phosphorylate other regulatory transcriptional proteins. 

Chromatin remodeling, transcription factor modification by various enzyme activities, and the communication between the nuclear receptors and the basal transcription apparatus are accomplished by protein-protein interactions with one or more of a class of coregulator molecules. The number of these coregulator molecules now exceeds 100, not counting species variations and splice variants. The first of these to be described was the CREB-binding protein, CBP. CBP, through an amino terminal domain, binds to phosphorylated serine 137 of CREB and mediates transactivation in response to cAMP. It thus is described as a coactivator. CBP and... 

Another important coactivator consists of 20 or more polypeptides in a protein complex called mediator (Fig. 28-27) the 20 core polypeptides are highly conserved from fungi to humans. Mediator binds tightly to the carboxyl-terminal domain (CTD) of the largest subunit of Pol II. The mediator complex is required for both basal and regulated transcription at promoters used by Pol II, and it also stimulates the phosphorylation of the CTD by TFIIH. Both mediator and TFIID are required at some promoters. As with TFIID, some DNA-binding transactivators interact with one or more components of the mediator complex. Coactivator complexes function at or near the promoter s TATA box. 

The CCAAT/enhancer-binding proteins (C/EBP) are transactivators known for their involvement in the regulation of acute phase and inflammatory protein expression [106]. The family comprises several isoforms, which can homo- and heterodimerize through their basic leucine zipper region [107], or associate with other transcription factors, including NF-kB [108, 109]. Activation of the C/EBP proteins involves their phosphorylation in a negative regulatory domain [110, 111]. In a similar manner to PU.l, some C/EBP family... 

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