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Transcriptional activation by the mouse oestrogen receptor

Danielian, Paul Shemavon; (1993) Transcriptional activation by the mouse oestrogen receptor. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The oestrogen receptor is a ligand inducible transcription factor that belongs to a family of nuclear receptor proteins. Previous studies have shown that in transient transfection experiments two regions of the oestrogen receptor protein are capable of stimulating transcription. One, located N-terminal to the DNA binding domain called transcriptional activation function 1, TAF-1, can stimulate transcription constitutively whilst TAF-2, located in the C-terminal hormone binding domain requires oestrogen binding for its activity. Analysis of mutant mouse oestrogen receptors has identified a region of the hormone binding domain important for TAF-2. The amino acid sequence in this region is conserved in other members of the nuclear receptor family. Point mutation of conserved hydrophobic residues practically abolished hormone dependent transcriptional stimulation by TAF-2 without affecting oestradiol or DNA binding. The ability of TAF-2 and TAF-1 to cooperate in stimulating transcription in the full-length receptor was also abolished by mutation of the conserved hydrophobic residues but not conserved acidic residues. Mutagenesis of the corresponding residues in the glucocorticoid receptor showed similar results indicating that these residues may be important for ligand inducible transcription by other members of the nuclear receptor family. A yeast genetic screen was established to identify target(s) for TAF-2 that were important for its ability to stimulate transcription. No candidate targets were identified but analysis of the TAF-2 defective mutants suggested that the mechanism whereby TAF-2 stimulates transcription in mammalian cells is not conserved in yeast. Finally the effects of mutations in the steroid binding domain upon transcriptional activation by the oestrogen receptor have been examined. One finding of these studies was that some mutations, that abolished oestradiol binding and transcriptional activation, did not affect transcriptional activation induced by another ligand indicating that while the binding sites for different ligands overlap they are distinct.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Transcriptional activation by the mouse oestrogen receptor
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10098049
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