Mediator complex transcriptional activation

Due to the complex structure of the initiation complex it remains imclear which interactions are responsible for the first mechanism. The coupling between the transactivat-ing domain and the initiation complex can be direct or indirect. There is evidence which indicates that proteins with co-activator function mediate the interaction between HRE-bound receptors and the transcription initiation apparatus. One such protein is RIP-140, which mediates the transcription activation of the estrogen receptor. The AF2 domain can also directly contact the transcriptional apparatus. One component of the RNA polymerase II holoenzyme, the SUGl protein, has been identified as a binding partner for the AF2 domain. The SUGl protein has the function of a co-acti-vator in transcription initiation and is considered a mediator (see 1.4.3.2). 

Downstream p53 signaling is mediated by transcriptional activation of specific genes and by complex formation between p53 and heterologous proteins. The most relevant downstream effectors of p53 identified to date are listed in Table II. 

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

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. 

Emi, Y., Ikushiro, S. and Iyanagi, T. (1996) Xenobiotic responsive element-mediated transcriptional activation in the UDP-glucuronosyltransferase family 1 gene complex. Journal of Biological Chemistry, 271, 3952-3958. 

Examples of co-activators are the steroid receptor co-activator (SRC) family [48] and the components of the mammalian mediator complex, which possesses chromatin remodelling ability and tethers activated steroid hormone receptors to the basal transcription machinery [49]. Additional co-... 

The potential impact of the chromatin structure on ERa- and ER/1-mediated transcriptional activities was investigated using an in vitro chromatin assembly assay. These experiments have shown that the AF-1 domain of ERa, but not of ER/1, contains a transferable activation domain, which permits the ERa to efficiently activate transcription on chromatin templates [58]. Furthermore, the co-activators CBP/p300 and SRC have to be recruited to the ERa in order to maximally enhance transcription on ERa-susceptible chromatin templates. The p300/CBP-SRC complex, when interacting with the AF-1 of the ERa, is primarily involved in the stable formation of the preinitiation complex of transcription [59]. 

---