Positive Regulation of Transcription

Positive regulation implies that the bound protein stimulates transcription. Such proteins are termed transcriptional activators. Transcriptional activation plays a central role in eukaryotes (see 1.4.3). There are various mechanisms of transcriptional activation. 

Usually protein-protein interactions between the transcriptional activator and components of the transcription apparatus are involved. 

---

Grundy FJ, Henkin TM. tRNA as a positive regulator of transcription antitermination in B. subtilis. Cell. 1993 74 475-482. 66. 

Laughon, A. and Gesteland, R.F. (1982) Isolation and preliminary characterization of the GAL4 gene, a positive regulator of transcription in yeast. Proceedings of the National Academy of Sciences of the United States of America, 79, 6827-6831. 

Figure 1 The MAPK pathway and its connections to other signals A negative feedback loop connects the phosphorylated endpoint of the pathway ERK (Extracellular-signal Regulated Kinase) to the transcriptionally-driven synthesis of the phosphatase, MKP MAP kinase phosphatase. MKP then de-phosphorylates ERK to shut down the signaling cascade. The positive feedback loop again starts with the terminal kinase ERK which activates cPLA2 (cytosolic phospholipase A2). This leads to the synthesis of arachidonic acid, which, in turn activates protein kinase C (PKC). PKC is a positive regulator of RAS (Please see Color Plate Section in the back of this book).

Overall, histone acetylation and deacetylation represents an important tool with which transcription can be positively or negatively influenced. The nucleosomes and, in a further sense, chromatin structure assiune a central role in the regulation of transcription. Nucleosome structure and nucleosome position can decisively contribute to the accessibility of DNA elements for transcription factors. The nucleosomes function as a framework that determines the spatial arrangement of a region of the DNA. Tlie nucleosome constellation must be modified during transcription initiation, whereby the post-translational modification of histones in the form of acetylation or deacetylation plays a significant role. The participation of other non-histone proteins remains an open issue and it is also imclear how a constitutive and permanent inactivation of a section of DNA can be accomplished via the chromatin structure. 

Driever, W. and Nusslein-Volhard, C. The bicoid protein is a positive regulator of hunchback transcription in the early Drosophila embryo (1989) Nature 337,138-143... 

Saito, K., Elce, J.S., Hamos, J.E., Nixon, R.A., 1993, Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease a potential molecular basis for neuronal degeneration, Proc. Natl. Acad. Sci. U.S.A., 90, 2628—2632 Saido, T., Shibata, M., Takenawa, T., Murofushi, H., Suzuki, K., 1992, Positive regulation of p-calpain action by polyphosphoinositides, J. Biol. Chem., 267, 24585—24590 Sandmann, S., Yu, M., Unger, T., 2001, Transcriptional and translational regulation of calpain in the rat heart after myocardial infarction - effects of AT( 1) and AT(2) receptor antagonists and ACE inhibitor, Br. J. Pharmacol. 132, 767-777... 

M. M. Barker, T. Gaal and R. L. Course (2001). Mechanism of regulation of transcription initiation by ppGpp. II. Models for positive control based on properties of RNAP mutants and competition for RNAP. J. Mol. Biol., 305, 689-702. 

Finally, in Plate 21, the structure of the yeast TFIIA-TBP-DNA complex is shown. TFIIA interacts with TBP and the TFIID complex and stimulates transcription of the Pol II gene.29-32 TFIIA has two characteristic structural motife. One is a six-stranded (i-sand-wich, the other is a left-handed four-helix bundle. The P-sandwich domain of TFUA is alone responsible for all of the interactions with the DNA, whereas its helix-bundle domain projects away and is free to interact with signal-responsive transcription factors. These interactions are important for regulation of transcription. Little conformational change occurs in TBP when it binds to TFIIA. The main difference between the TFIIA-TPB complex and the TFIIB-TBP complex is that TFIIA binds upstream of the TATA box, away from the transcriptional start site, whereas TFIIB binds downstream of the TATA box. Moreover, TFIIB is positioned on the side opposite to TFIIA. 

Jaeschke A, Karasarides M, Ventura JJ, Ehrhardt A, Zhang C, Flavell RA, Shokat KM, Davis RJ. JNK2 is a positive regulator of the cJun transcription factor. Mol. Cell. 2006 23 899-911. Ventura JJ, Hubner A, Zhang C, Flavell RA, Shokat KM, Davis RJ. Chemical genetic analysis of the time course of signal transduction by JNK. Mol. Cell. 2006 21 701-710. 

---