Characterisation of Human Oestrogen Receptor beta (ERβ) Splice Variants in Neuronal Cells

Abstract

Oestrogen receptor (ER)α and ERβ are members of the ligand-activated superfamily of nuclear receptors and mediate most facets of oestrogen signalling. Several naturally occurring splice variants of each ER have been identified in the human brain, yet the biological significance of these splice variants in the brain remains unknown. In the present study, we exploit the unique structural differences of the human ERβ splice variants to determine the functional significance of individual ER domains in the brain. We previously established that full-length rodent ERβ (i.e. rERβ1) has constitutive transcriptional activity in neuronal cells in the absence of ligand. By contrast to the rodent splice variants, the human ERβ splice variants used in the present study contain varying length truncations of exon 8, which encodes for the E/F domains. Our results reveal that, in neuronal cells, each human-specific ERβ splice variant constitutively activated promoters mediated by a canonical oestrogen response element and repressed promoters mediated by activator protein-1 sites via p38 activity. From these data, we conclude that the C-terminus, encoding the AF-2 region and F domain, is not essential for the constitutive properties of human ERβ. Taken together, these studies show that human-specific ERβ variants are constitutively active and also provide novel insight into the contributions of the functional domains of ERβ towards mediating constitutive transcription at various promoters in neuronal cells.