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The regulation of transcription factors is a highly complex process as it is dependent upon a number of events, most notable of which are the presence of other DNA binding proteins (including other transcription factors) as well as local chromatin structure. Initial models, based on in vitro expreriments suggested that there is a definite assembly sequence of transcription factors dictated by the DNA sequence. It is, however, becoming incresingly obvious that the events leading to activation of transcription are dependent on a large number of factors and are highly intertwined. Furthermore epigenetic information present on DNA appears to play an important role in transcriptional activation.
Contents |
Classes
There are three classes of transcription factors:
- General transcription factors are involved in the formation of a preinitiation complex. The most common are abbreviated as TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH. They are ubiquitous and interact with the core promoter region surrounding the transcription start site(s) of all class II genes.
- Upstream transcription factors are proteins that bind somewhere upstream of the initiation site to stimulate or repress transcription.
- Inducible transcription factors are similar to upstream transcription factors but require activation or inhibition.
General Definition- Protein involved in recognition by RNA polymerases of specific regulatory sequences in eukaryotic genes.
DNA motifs found in transcription factors
- Helix-turn-helix (HTH) bind the major groove of the
DNA.
Zinc fingers function as structural platforms for DNA binding.
Leucine zippers function in associating the transcription factors with each other.
Basic-helix-loop-helix (bHLH) bind DNA with two alpha helices containing basic amino acid residues which are linked by a loop and are typically dimeric.
G-quadruplex Motifs are a focus for current studies in their role as a TF binding site.
Examples of transcription factors
STAT
The Signal Transducers and Activator of Transcription (STAT) proteins regulate many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced survival of tumors. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
Function of STAT proteins
STAT proteins were originally described as latent cytoplasmic transcription factors that require phosphorylation for nuclear retention. The unphosphorylated STAT proteins shuttle between the cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reach the nucleus, they bind to a consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine-inducible genes and activate transcription of these genes.
Activation of STAT proteins
Extracellular binding of Cytokines induces activation of the intracellular Janus kinase that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization of STAT monomers via their SH2 domain. The phosphorylated dimer is then actively transported in the nucleus via importin a/b and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription of this proteins. The STAT protein can be dephosphorylated by nuclear phosphatases which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP.
