title: Expression of oestrogen receptor beta isoforms is regulated by transcriptional and post-transcriptional mechanisms.
abstract: Although ERs (oestrogen receptors) mediate breast tumour behaviour, the precise role of ERbeta remains unclear. This is mainly because analyses have been complicated by the presence in breast tissue of three ERbeta protein variants (ERbeta1, ERbeta2 and ERbeta5) that derive from differential 3' splicing. We have recently identified the first known mechanisms responsible for the differential control of isoform expression, involving regulation of translation via 5'-UTRs (untranslated regions). In the present study, we have uncovered further complexity involving the influence of multiple promoters and cross-talk between 5'- and 3'-UTRs. We demonstrate that full-length ERbeta mRNAs are transcribed from three separate promoters; two promoters are well-established within the literature, whereas the third represents a novel finding. Each promoter produces transcripts with distinct 5'-UTRs. The differential 3' splicing that produces transcripts coding for the ERbeta isoforms also defines isoform-specific 3'-UTRs. We identified exact 3'-UTR sequences for each isoform, and have shown that alternative polyadenylation sites are used in a cell-type specific manner to produce transcripts with 3'-UTRs of different lengths. Critically, we show that 5'- and 3'-UTRs combine to specify the efficiencies with which individual transcripts are translated, with 3'-UTR length having a key influence. In addition, we demonstrate how 17beta-oestradiol, a key driver of breast cancer development, affects the regulation of ERbeta expression at both transcriptional and translational levels.
authors.affiliation: Leeds Institute of Molecular Medicine, Leeds University, Leeds LS9 7TF, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Smith
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Coleman
authors.forename: Michele
authors.initials: M
authors.lastname: Cummings
authors.forename: Sampoorna
authors.initials: S
authors.lastname: Satheesha
authors.forename: Spencer O
authors.initials: SO
authors.lastname: Shaw
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hughes
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D047629:Estrogen Receptor beta; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004958:Estradiol