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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
1 Correspondence to James Eberwine, Department of Pharmacology, University of Pennsylvania Medical Center, 36th and Hamilton Walk, Philadelphia, Pennsylvania 19104.
Transcription factors are categorized as trans-acting factors because they are regulatory agents which are not part of the regulated gene(s). These trans-acting factors regulate gene transcription by binding directly or through an intermediate protein to the gene at a particular DNA sequence, called a cis-regulatory region. This cis-regulatory region is usually located in the 5′-flanking promoter region of the gene and is composed of a specific nucleotide sequence, for example, the cAMP response element (consensus sequence TGACGTCA). There is also a class of cis-regulatory elements called enhancers, which can be positioned anywhere in a gene and, consequently, are not restricted to the promoter region, which bind, for example, the glucocorticoid receptor. Binding of the trans-acting factor to the cis-regulatory region alters the intiation of transcription, probably through a direct interaction of the trans-acting factor with the RNA—polymerase complex. This binding likely occurs through the secondary and tertiary structures of the genomic DNA—protein complexes. Usually, transcription factors bind as dimers to the DNA, suggesting that there are dimerization sites on transcription factors, as well as DNA-binding sites. There are several types of transcription factors, which are grouped by virtue of sequence similarities in their protein interaction and/or DNA-binding domains (Fig. 26-3). Similarities in protein—protein interaction sites suggest that monomers of different transcription factors can interact to form heterodimers. An individual heterodimer may bind to multiple cis-acting elements or, alternatively, interact with differing affinity for the same cis-acting element as compared with the homodimer. Indeed, these types of protein interactions do occur and provide a major source of regulatory complexity.
Structure of transcription factors from different families.
A particular cis-acting element may be present in multiple genes so that activation of a single transcription factor has potential for altering the expression of multiple target genes. Furthermore, an individual transcription factor may increase transcription of one gene while decreasing the transcription of another gene. This difference is partly due to the positioning of the cis-acting element relative to the start of transcription as well as to the identity of the protein partners in the heterodimer complex. It is important to note that, with the increase in sequence information being generated by the Human Genome Project, cis-acting elements can be found in genes, suggesting potential gene regulatory mechanisms without any biological information. While cis-acting element sequence identification in a gene is indeed predictive and necessary, this is often not sufficient to fully characterize the transcriptional regulation of that gene. cis-Acting elements for a particular gene are commonly nonfunctional in all tissues and, even more often, silent in one tissue and active in another due to the differential distribution of transcription factors.
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