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GTS351 Theme 8 summary
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GENE CONTROL AND CELLULAR SIGNALLINGPATHWAYS
Regulation of transcription factors
- TFs need to be differentially active and have activity modulated by
specific stimuli
- Method 1: slow
- Regulates TF synthesis
- Frequently used for expression over a long time
- E.g. cell-type specific or developmental regulated genes
- Second TF required to regulate transcription of 1st TF
- Solution is post-transcriptional regulation
- Method 2: fast
- Regulates TF activity
- Involves alteration of a pre-existing protein
- More rapid response
- Mechanisms to regulate TF activity
- Direct binding of ligand to TF
- Phosphorylation of TF
- Proteolytic cleavage of TF
- Regulation of protein-protein interactions
,Regulation of TFs by ligands that enter the cell
- E.g. steroid hormones
- After binding to the ligand (steroid hormone), steroid receptors often
form dimers
- In the nucleus, complex acts as a transcription factors, augmenting or
suppressing transcription of particular genes by its action on DNA
- Glucocorticoid and steroid receptors
- Located in cytosol bound to HSP90
- Binding of hormone causes conformational changes resulting in:
- HSP90 dissociation
- Exposure of nuclear localisation signal of receptor and
interaction with nuclear-import proteins
- Exposes domains essential for binding to DNA and
transcription
- Binding of glucocorticoid to the glucocorticoid receptor results in its
dissociation from HSP90
- Movement of hormone-receptor complex to
nucleus activates the transcription of
glucocorticoid-responsive genes
, Glucocorticoid receptors
- Can repress or activate gene transcription
- Mechanism 1:
- Occurs through blocking another TF
- Glucocorticoid-hormone receptor complex binds to GRE DNA
sequence as a dimer
- Recruits correct factors to activate transcription
- Trimers bind to nGRE sequence
- nGRE sequences resemble naive GRE sequences but are not
identical
- Blocks binding of other activating factors
- Represses transcription
- Mechanism 2:
- Inhibition of transcription elongation
- Activated glucocorticoid receptor prevents recruitment of pTEF-b
kinase
- No phosphorylation of ser 2 of RNA pol II is a prerequisite for
transcriptional elongation
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