Transcription activator Mechanism

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. 

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. 

Phillips, B., Abravaya, K., Morimoto, R.l. (1991), Analysis of the specificity and mechanism of the transcriptional activation of the human hsp70 gene during infection by DNA viruses. J. Virol. 11, 5680-5692. 

Keaveney M, Struhl K Activator-mediated recruitment of the RNA polymerase machinery is the predominant mechanism for transcriptional activation in yeast. Mol Cell 1998 1 917. Lemon B, Tjian R Orchestrated response a symphony of transcription factors for gene control. Genes Dev 2000 l4 255l. Maniatis T, Reed R An extensive network of coupling among gene expression machines. Nature 2002 416 499. 

Cosma MP (2002) Ordered recruitment gene-specific mechanism of transcription activation. Mol Cell 10(2) 227-236... 

Temple JL, Laing E, Sunder A, Wray S (2004) Direct action of estradiol on gonadotropin-reelasing hormone-1 neuronal activity via a transcription-dependent mechanism. JNeurosci 24 6326-6333... 

Gibson, G.G., Plant, N.J., Swales, K.E., Ayrton, A. and El-Sankary, W. (2002) Receptor-dependent transcriptional activation of cytochrome P4503A genes induction mechanisms, species differences and interindividual variation in man. Xenobiotica, 32 (3), 165-206. 

A system such as this can provide a powerful mechanism for transcriptional control. While bound to nucleosomes, PARP-1 promotes a transcriptionally repressed state, but one that is simultaneously poised for activation because of the allosteric activating effect of nucleosomes on PARP-1 enzymatic activity. In the presence of NAD+, PARP-1 can autoPARylate and release from nucleosomes, shifting the chromatin to a more transcriptionally active conformation. PARC can reset the system by cleaving the PAR chains from PARP-1, allowing PARP-1 to re-bind the nucleosomes and re-establish a transcriptionally repressed state. 

Recent studies demonstrate that histone H2B phosphorylation also plays a key role in the response to DNA double-strand breaks, apoptosis, meiosis and transcription activation events. However, the details of this mechanism are poorly understood. 

Rahman MS, Yang J, Shan LY, Unruh H, Yang X, Halayko AJ, Gounni AS IL-17R activation of human airway smooth muscle cells induces CXCL-8 production via a transcriptional-dependent mechanism. Clin Immunol 2005 115 268-276. 

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