Biological Sciences
Transcription Factors
Transcription factors are proteins that regulate the transcription of specific genes by binding to DNA. They play a crucial role in controlling gene expression and are involved in various cellular processes such as growth, development, and response to environmental stimuli. By binding to specific DNA sequences, transcription factors can either activate or repress the transcription of target genes, thereby influencing the production of specific proteins.
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10 Key excerpts on "Transcription Factors"
- Sinha, Asha(Authors)
- 2018(Publication Date)
- Biotech(Publisher)
Thus, gene regulation is essential to life- from the simplest virus to the most complex mammal. The transcription of DNA to make messenger RNA is highly controlled by the cell. In order for a higher organism (plant or animal) to function, genes must be turned on and off in coordinated groups in response to a variety of situations. For a plant this may be abiotic (non-living) stress such as the rising or setting sun, drought, or heat, biotic (living) stress such as insects, viral or bacterial infection, or any of a limitless number of other events. The job of coordinating the function of groups of genes falls to proteins called Transcription Factors (TxF's). Any protein which is essential for the initiation of transcription is called as a transcription factor. Transcription factor or sequence-specific DNA binding factor is a protein, recognizing the cis-acting sites that are the parts of the promoters or enhancers region of the DNA, which controls the flow of genetic information from DNA to mRNA. It performs the function alone or with other proteins by forming a complex, by promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to specific genes. Transcription Factors are able to bind to specific sets of short This ebook is exclusively for this university only. Cannot be resold/distributed. conserved sequence contained in each promoter. Transcription Factors are found in all living entities and are essential to regulate the expression of the gene. The number of TxF's varies from organism to organism which is also increased according to the increasing genome size. Current status showed that there are approximately 2600 proteins encoded by the human genome (10 per cent of the gene of the human genome) and most of them contain DNA binding domains and act as a TxF's.
- Eugene P Dimagno, Alberto Maringhini(Authors)
- 1999(Publication Date)
- World Scientific(Publisher)
In this article, we will use the general term of transcription factor to refer to this latter group of sequence-specific binding proteins. Transcription Factors are most often grouped into different structural families based primarily on their DNA-binding domain. The best characterized of these families include the homeobox, zinc finger, basic leucine zipper, basic helix-loop-helix, Rel-homology, Ets, and STAT families (30-32). Interestingly, members within each of these families of Transcription Factors have been shown to regulate genes important for cell growth and differentiation (8, 33-40). Furthermore, recent evidence indicates that these families of Transcription Factors are expressed in 15 Figure 1: Structure and function of a sequence-specific transcription factor, a) Diagram of the structural domains most often found in Transcription Factors. The DNA-binding motif recognizes specific cw-regulatory sequences present in the promoter of a particular gene, the transcriptional regulatory domain can act to either repress or activate transcription, and the nuclear localization signal allows the import of the transcription factor into the nucleus. Any or all of these domains can be modified by signal-mediated post-translational modifications to alter the function of a transcription factor, b) Diagram representing eukaryotic transcription. The expression of specific genes is mediated through cw-regulatory sequences located in promoter and enhancer elements upstream of the coding sequence. RNA polymerase II and its associated factors together form a multimeric protein complex, tie basal transcriptional machinery, which initiates the synthesis of mRNA of most genes by binding to promoter sequences. Sequence-specific Transcription Factors bind to enhancer elements and interact with the basal transcriptional apparatus to either activate or repress transcription.
eBook - PDF- Pavel Pevzner, Ron Shamir(Authors)
- 2011(Publication Date)
- Cambridge University Press(Publisher)
Indeed, the task is complex even for the much simpler case in which the substrate is a nucleic acid molecule (DNA or RNA). While the general principles are common to both proteins and nucleic acids, for the sake of simplicity, we will restrict the exposition to nucleic acids hereafter. In particular, we will discuss the issue of modeling the DNA sites recognized and bound by Transcription Factors (TF), i.e. transcription factor binding sites (TFBS). To orient the reader, we next provide a brief introduction to transcriptional regulation. 128 Part II Gene Transcription and Regulation Polymerase Transcription Initiation Site Adaptor protein Figure 7.1 Transcription factor proteins (filled ellipses) interact with binding sites (filled rectangles) in the relative vicinity of a gene transcript (black rectangle). The transcription factor binding sites can either be proximal to the transcript (within a few thousand nucleotides) or far (several hundred thousand nucleotides). The interactions between Transcription Factors is aided by other adaptor proteins. The DNA-bound Transcription Factors interact with polymerase to regulate transcription. How much, at what time, and where within an organism any gene product is pro-duced is precisely regulated, and is critical to maintaining all life processes. While the overall regulation of a gene product is executed at various levels – including splicing, mRNA stability, export from nucleus to cytoplasm and translation – much of this regulation is accomplished at the level of transcription. Transcriptional regulation is a fundamental cellular process, and aberrations in this process underlie many diseases [3] . For example, mutations in the Factor IX protein is known to cause hemophilia B. Additionally, mutations in the regulatory region immediately upstream of Factor IX gene can disrupt the binding of specific TF, which in turn dysregulates the transcription of the gene, thus leading to hemophilia [3] .
eBook - PDF- Lizabeth A. Allison(Author)
- 2021(Publication Date)
- Wiley-Blackwell(Publisher)
Usually Transcription Factors are depicted in figures acting as single molecules. But results from single-molecule fluorescence microscopy suggest that Transcription Factors function in clusters of 7–10 molecules, termed “nano-footballs.” The clusters, as you might have already guessed, are proposed to be stabilized by intrinsically disordered regions. Nano-footballs are thought to roll along segments of DNA and hop to other nearby segments to find specific genes more quickly. Transcription Factors mediate gene-specific transcriptional activation or repression Transcription Factors that serve as repressors block the general transcription machinery, whereas Transcription Factors that serve as activators increase the rate of transcription by several mechanisms: 1 Stimulation of the recruitment and binding of general Transcription Factors and RNA polymerase II to the core promoter to form a preinitiation complex. 2 Induction of a conformational change or post-translational modification such as phos-phorylation that stimulates the enzymatic activity of the general transcription machinery. 3 Interaction with chromatin remodeling and modification complexes to permit enhanced accessibility of the template DNA to general Transcription Factors or specific activators. These different roles can be promoted directly via protein–protein interaction with the general transcription machinery or via interactions with transcriptional coactivators and corepressors, described in the next section. Many Transcription Factors are members of multiprotein families. For example, nuclear receptors are members of a superfamily of related proteins, including the receptors for ster-oid hormones, thyroid hormone, and vitamin D. NF-κ B is yet another family of proteins, and Sp1 – one of the first Transcription Factors to be isolated – is a member of the Sp fam-ily of proteins.
No longer available |Learn more- David Latchman(Author)
- 2020(Publication Date)
- Garland Science(Publisher)
5.16 ). As discussed in the next two sections, the recruitment of co-activators and co-repressors by DNA-bound transcriptional activators or repressors, respectively, plays a critical role in transcriptional activation or repression. Thus, differences in the factors recruited by a factor bound to different DNA sequences will play a significant role in determining its effect on the transcription of its target genes.5.2 Activation of Transcription
Although binding of Transcription Factors to DNA is generally a necessary prerequisite for the activation of transcription, it is clearly not in itself sufficient for this to occur. Following binding, the bound transcription factor must somehow regulate transcription, for example, by directly activating the RNA polymerase itself or by facilitating the binding of other Transcription Factors and the assembly of a stable transcriptional complex or by recruiting chromatin remodeling complexes.Activation domains can be identified by “domain-swap” experiments
It is clear from Section 5.1 of this chapter that Transcription Factors have a modular structure in which a particular region of the protein mediates DNA binding, while another may mediate binding of a co-factor such as a hormone, and so on. It seems likely, therefore, that a specific region of each individual transcription factor will be involved in its ability to up-regulate transcription following DNA binding.In the majority of cases, it is clear that such activation regions are distinct from those that produce DNA binding. This domain-type structure is seen clearly in the yeast transcription factor GCN4, which mediates the induction of the genes encoding the enzymes of amino acid biosynthesis in response to amino acid starvation. If a 60 amino acid region of this protein containing the DNA-binding domain is introduced into cells, it can bind to the DNA of GCN4-responsive genes but fails to activate transcription. Although DNA binding is necessary for transcriptional activation to occur, it is not therefore sufficient, and gene activation must be dependent upon a region of the protein that is distinct from that mediating its binding to DNA.
eBook - ePubMolecular Pharmacology
From DNA to Drug Discovery
- John Dickenson, Fiona Freeman, Chris Lloyd Mills, Christian Thode, Shiva Sivasubramaniam, Christian Thode(Authors)
- 2012(Publication Date)
- Wiley(Publisher)
Drugs that target specific moieties on Transcription Factors such as phosphorylation sites, nuclear localisation domains, DNA binding sites, or co-activator(s) interaction sites have been developed for the treatment of tumourgenesis. However, this approach can lead to the development of drugs that target regions that could be conserved in other proteins. So unless compartment specific therapies can be developed the side effects of these drugs would be unacceptable. This has led researchers to develop strategies that determine which genes are regulated by these ‘transcription factor-mediating’ drugs. Employment of reporter gene assays (e.g. green fluorescent protein; GFP) would create large libraries that can be analysed to determine which transcription factor(s) are affected by these drugs. This would allow the development of transcription factor specific agonists and antagonists. In fact this approach has led to development of an inhibitor of a transcription factor STAT1 (signal transducer and activator of transcription 1); 2-(1,8-naphthyridin-2-yl)phenol (2-NP). This transcription factor is implicated in cancer formation and 2-NP has been shown to reduce proliferation in breast cancer studies (Lynch et al., 2007). Nifuroxazide is another anti-cancer drug that has been shown to be a potent inhibitor of the transcription factor, STAT3 function as well as possessing anti-proliferation activity (Nelson et al., 2008).8.4 Nuclear receptors
Nuclear receptors (NR) are Transcription Factors that can facilitate or repress gene expression. Ligands or metabolic factors can enter the cell and either activate NRs in the cytoplasm so that they enter the nucleus or activate nuclear located NRs. Once activated the NR can alter gene expression as monomers, homodimers or as heterodimers with, for example, the retinoic acid receptor (RAR). There is considerable debate in the literature as to how NRs evolved. The current view is that they evolved from environmental sensors where extracellular factors enter the cell enabling the cell to adapt to changing environments. This theory is compelling because in animals NRs play an important role in homeostasis, development and growth. In addition, NRs can be activated by ligand binding or their activity can be modulated by the activity of signalling pathways within the cell.
eBook - PDF- Rajeev K. Varshney, Robert M.D. Koebner, Rajeev K. Varshney, Robert M.D. Koebner(Authors)
- 2006(Publication Date)
- CRC Press(Publisher)
When compared, the binding spec-ificity of individual members of a TF family displays slight differences [49,72], which are likely of regulatory significance in determining target site selection and gene expression parameters in vivo . 8.2.3.2 Transeffector Properties A key function of TFs is to recruit the transcriptional machinery to specific gene promoters [9]. This is achieved through direct interactions with one or more general TFs or indirectly through cofactors (coactivators) that do not bind DNA. Several classes of coactivator have been described [77,78]. Many comprise large multiprotein complexes that possess chromatin remodeling and/or modifying activities. These activities facilitate access of TFs and the basal transcriptional machinery to specific gene promoters. Conversely, transrepression domains may interact with co-repressors possessing chromatin remodeling and/or modifying activities that impede access of the basal transcriptional machinery. Transcription factor interfaces responsible for recruiting the preceding classes of proteins are called effector (transactivation or transrepression) domains. The specific amino acid sequences and structural features required to create effector domains are not as well defined as those responsible for DNA binding. Many transactivation domains are rich in acidic amino acids; others are rich in glutamine or isoleucine [9]. Repression domains have been characterized as being charged, rich in alanine or in alanine and proline [79]. Proline-rich domains have been implicated in transcriptional activation and repression. It is also possible for indi-vidual TFs to display transactivation and repression properties. The cell-specific concentration of a TF as well as the presence and concentration of interacting proteins are factors that may determine its ability to transactivate vs.
eBook - PDF- Franklyn F. Bolander(Author)
- 2013(Publication Date)
- Academic Press(Publisher)
Finally, p50 can be activated by the proteolytic removal of its inhibitory carboxy terminus; this modification is stimulated by PKC (118) and is obviously irreversible. Protein-protein interactions represent a fourth mechanism. There are three types of interactions: (i) inhibitors, (ii) dimerization partners, and (iii) cofactors. Inhibitors would include IP-1 and ΙκΒ which bind and block the DNA binding of AP-1 and NF-JCB, respectively; in both cases, phosphoryl-ation causes dissociation of the inhibitor. The heat shock proteins and steroid receptors represent other examples; here, dissociation follows ligand binding. As noted earlier, most Transcription Factors are dimers whose partners can come from any member within a particular family; indeed, dimerization between families has also been reported (see subsequent discussion). Tran-scriptional activity, HRE preference, and regulation are often influenced by the kinds of partners present in the dimer; for example, Myc-Max stimulates transcription whereas Mad-Max inhibits it, and Jun-Jun prefers to bind the sequence TGACATCA whereas Jun-Fos binds TGACTCA. Finally, the tran-scription factor may require auxiliary proteins, which may be regulated themselves. For example, SCF requires TCF, whose propensity for ternary complex formation is controlled by MAPK; ISGFl-ISGFy requires ISGFa, whose intracellular localization is regulated by tyrosine phosphorylation. Fifth, Transcription Factors can be regulated by compartmentalization (162). This subcellular localization can be controlled by several mechanisms. First, nuclear migration can be induced by the phosphorylation of either the DNA-binding component or some other regulatory subunit; Rel and C/EBP/? are examples of the former, and ISGF3a is an example of the latter. Nuclear localization can also be stimulated by dephosphorylation: NF-AT is a T-cell transcription factor that migrates to the nucleus after it is dephosphorylated
eBook - PDFTranscription Factors in the Nervous System
Development, Brain Function, and Diseases
- Gerald Thiel(Author)
- 2006(Publication Date)
- Wiley-Blackwell(Publisher)
During development, many dif- ferent cell types are generated that carry, with the exception of developing lympho- cytes, the same genetic information. Tight control of gene expression is required for 114 6 RE–1 Silencing Transcription Factor (REST) acquisition of distinct cellular identities by the differentiating cells. Only a fraction of the genes in the genome is expressed in every cell type. Those genes encode proteins necessary for the survival of the cell – that is, metabolic enzymes or struc- tural proteins. In contrast, a portion of the genes is transcribed only in particular cell types. The tissue-specific expression of these genes is the molecular basis for the striking differences of the many cell types found in a multicellular organism. The differential expression of tissue-specific genes is thus responsible for the develop- ment of a variety of cell types such as neurons, lymphocytes, endothelial cells, he- patocytes, myocytes and astrocytes, that all together build up the organism. Alterations in gene expression are, therefore, the basis for the understanding of multicellular organisms. Neurons differ from other cells of an organism by contain- ing a specific set of proteins that are crucial for the execution of the specialized functions of the nervous system. These proteins are encoded by genes that must be expressed in a neuron-specific manner. The regulatory mechanisms that control gene expression in neurons are therefore fundamental for the development and function of the brain. Many neuronal genes are expressed throughout the nervous system, indicating that Transcription Factors are required that ensure continuous active control of neuron-specific gene transcription in every neuron throughout adulthood. One regulator protein has been discovered, in the analysis of neuronal gene expression, that may fulfill this role.
eBook - PDF- David S. Latchman(Author)
- 2003(Publication Date)
- Academic Press(Publisher)
Indeed, the ability of different molecules of the same factor or different activating factors to interact with different components within the basal tran-scriptional complex is likely to be essential for the strong enhancement of transcription which is the fundamental aim of activating molecules (Fig. 5.30) (for review see Carey, 1998). 5.5 OTHER TARGETS FOR TRANSCRIPTIONAL ACTIVATORS Although the basal transcriptional complex which initiates transcription is the best characterized target for transcriptional activators and co-activators (as discussed in the preceding sections) at least two other stages of the transcrip-tional process can be targeted by such activators and these will be discussed in turn. 5.5.1 MODULATION OF CHROMATIN STRUCTURE As discussed in Chapter 1 (section 1.2), the DNA molecule is associated with histones and other proteins to form particles known as nucleosomes which 162 EUKARYOTIC Transcription Factors Figure 5.30 The ability of multiple activating molecules (A) to contact different factors allows strong activation of transcription. are the basic unit of chromatin structure. Prior to the onset of transcription, the chromatin structure becomes altered thus allowing the subsequent bind-ing of the factors which actually stimulate transcription. This alteration in chromatin structure can itself be produced by the binding of a specific tran-scription factor. This results in a change in the nucleosome pattern of DNA/ histone association thereby allowing other activating factors access to their specific DNA binding sites (Fig. 5.31). Thus, as discussed in Chapter 1 (section 1.3.3), genes whose transcription is induced by elevated temperature share a common DNA sequence which, when transferred to another gene, can render the second gene heat inducible. This sequence is known as the heat shock element (HSE).
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