Cowley, Shaun Michael; (1998) Transcriptional activation and dimerisation properties of oestrogen receptor β. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The oestrogen receptor (ER) is a member of the nuclear receptor superfamily of ligand inducible transcription factors. In the absence of oestrogen the ER exists in the cell as part of an inactive complex with heat shock proteins. Upon binding oestrogen the heat shock proteins are displaced, and the ER is able to bind DNA as a dimer where it stimulates transcription from oestrogen responsive elements (ERE) in the vicinity of target genes. The ER exists in two forms, the classical ERα and the recently discovered ERβ, which are encoded by distinct genes. ERβ has a similar binding affinity for 17β-oestradiol as ERα and is capable of activating transcription from ERE containing promoters. When co-expressed in vitro or in vivo ERα and ERβ form heterodimers, which bind to an ERE with an affinity similar to that of ERα homodimers but greater than that of ERβ homodimers. The heterodimer, like the homodimers, are capable of binding the steroid receptor coactivator 1 (SRC1) when bound to DNA and stimulating transcription from ERE containing reporter genes in cell lines. ERα has two well characterised transcriptional activation domains, activation function 1 (AF1) in the N-terminus and activation function 2 (AF2) in the C-terminus. A comparison of the AF1 and AF2 domains from ERα and ERβ revealed that ERβ does not have an AF1 activity equivalent to that of ERα, while their AF2 activities are similar. Nuclear receptors stimulate transcription by interacting with the SRC1 family of coactivator proteins. We have isolated a fragment of an SRC1 family member from chicken which we term, Chip1. Chip1 is highly homologous to other SRC1 coactivators and is able to interact with ERα in a ligand-dependent manner. Southern blotting analysis revealed that similar to humans, chickens contain three SRC1 coactivator genes. The conservation of sequence and number of SRC1 coactivators suggests that nuclear receptors retain a largely conserved mechanism of transcriptional activation.

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