Transcriptional control

In the resting state, the lysine residues in the N-terminal tail of the histones (see p. 238) are not acetylated. In this state, which can be produced by histone deacetylases [1], the nucleosomes are stable. It is only the interaction of activator and regulator proteins with their control elements that allows the binding of coactivator complexes that have histone acetylase activity [2]. They acetylate the histone tails and thereby loosen the nu-cleosome structure suf ciently for the basal transcription complex to form. 

This consists of DNA-dependent RNA polymerase II and basal transcription factors (TFIIX, X = A - H). First, the basal factor TFIID binds to the promoter. TFIID, a large complex of numerous proteins, contains TATA boxbinding protein (TBP) and so-called TAFs (TBP-associated factors). The polymerase is attached to this core with the help of TFIIB. Before transcription starts, additional TFs have to bind, including TFIIH, which has heli-case activity and separates the two strands of DNA during elongation. In all, some 35 differ- 

The actual signal for starting elongation consists of the multiple phosphorylation of a domain in the C-terminal region of the polymerase. In phosphorylated form, it releases itself from the basal complex along with a few TFs and starts to synthesize hnRNA. 

Phosphoenolpyruvate carboxykinase (PEP-CK), a key enzyme in gluconeogenesis, is regulated by several hormones, all of which affect the transcription of the PEP-CK gene. Cortisol, glucagon, and thyroxin induce PEP-CK, while insulin inhibits its induction (see p. 158). 

Koolman, Color Atlas of Biochemistry, 2nd edition 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 

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Regulatory regions are transcriptional control sequences, which consist of promoters, response elements, enhancers and possibly silencers, located upstream of the start site of transcription. The overall effect on gene transcription is a sum of the contributions of these elements and the activities of proteins recruited to these sites. Promoters are located immediately upstream of the start site and initiate transcription. They often contain tissue- or cell-specific elements if the gene is not ubiquitously expressed. Enhancers are positive regulatory elements which function independently of orientation and distance from the genes they regulate. 

The modulation of transcription nicely demonstrates how results of basic science can be translated into medical application. These few examples of drugs in successful use stimulate at the same time the intensive study of gaps in our understanding of transcriptional control, hoping to find new specific ways of interference. 

Kramer BP, Eischer C, Fussenegger M. BioLogic gates enable logical transcription control in mammalian cells. Biotechnol Bioeng 2004 87 478-84. 

DNA in transcriptionally active tegions is sensitive to nuclease attack some tegions are exceptionally sensitive and are often found to contain transcription control sites. 

Table 37-3. Some of the transcription control elements, their consensus sequences, and the factors that bind to them which are found in mammalian genes transcribed by RNA polymerase II. A complete list would include dozens of examples. The asterisks mean that there are several members of this family.

Transcription controls operate at the level of protein-DNA and protein-protein interactions. These interactions display protein domain modularity and high specificity. 

Ghromatin modifications are important in eukaryotic transcription control. 

Point mutations Protein folding Transcriptional control Frameshiftand nonsense mutations RNA processing Sickle cell disease P-Thalassemia P-Thalassemia P-Thalassemia... 

Induction of phase II enzymes, which conjugate reactive electrophiles and act as indirect antioxidants, appears to be the means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part,... 

Cellular and extra-cellular environment regulatory genes transcription control... 

The novel mechanism of transcriptional control of the ferric citrate transport system via transmembrane signalling is also observed in Pseudomonas putida and probably also occurs in Pseudomonas aeruginosa. Synthesis of the PupB outer... 

Newton, R. et al. Evidence for involvement of NF-kappaB in the transcriptional control of COX-2 gene expression by IL-lbeta. Biochem. Biophys. Res Commun. 237, 28, 1997. 

Dixon, D. A. et al. Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3 -untranslated region. J. Biol. Chem. 275, 11750, 2000. 

Crosa, J. H. (1997). Signal transduction and transcriptional and post transcriptional control of iron-regulated genes in bacteria, Microbiol. Mol. Biol. Rev., 61, 319-336. 

Thummel KE, Brimer C, Yasuda K, Thottassery J, Senn T, Lin Y, Ishizuka H, Kharasch E, Schuetz J, Schuetz E (2001) Transcriptional control of intestinal cytochrome P-4503A by 1-alpha, 25-dihydroxy vitamin D3. Mol Pharmacol 60 1399-1406. 

Auwerx, J., Schoonjans, K., Fruchart, J. C., and Staels, B. (1996). Transcriptional control of triglyceride metabolism Fibrates and fatty acids change the expression of the LPL and apo C-111 genes by activating the nuclear receptor PPAR. Atherosclerosis 124(Suppl.), S29-S37. 

Norris, T. L., Kingsley, R. A., and Bumler, A. J. (1998). Expression and transcriptional control of the Salmonella typhimurium Ip/fimbrial operon by phase variation. Mol. Microbiol. 29, 311-320. 

Doucas, V., The promyelocytic (PML) nuclear compartment and transcription control. Biochem Pharmacol, 2000, 60(8), 1197-201. 

The SCF and SCF-like complexes are multi-subunit RING-type E3s that represent the largest E3 family knotvn to date. This superfamily of E3s are involved in regulating cell-cycle progression, signal transduction pathways, transcriptional control, and multiple aspects of cell growth and development (reviewed in Ref. [50]). All members of this E3 superfamily contain two basic components, a member of the cullin protein family and a RING-domain protein. The cullin subumt serves as the... 

Among the several ubiquitin-like modifiers, SUMO is highly conserved from yeast to human and has been shown to regulate a variety of cellular functions such as nucleocytoplasmic transport, signal transduction, and transcriptional control... 

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