title: Estrogen receptor-α recruits P-TEFb to overcome transcriptional pausing in intron 1 of the MYB gene.
abstract: The MYB proto-oncogene is expressed in most estrogen receptor-positive (ERα(+)) breast tumors and cell lines. Expression of MYB is controlled, in breast cancer and other cell types, by a transcriptional pausing mechanism involving an attenuation site located ∼1.7 kb downstream from the transcription start site. In breast cancer cells, ligand-bound ERα binds close to, and drives transcription beyond this attenuation site, allowing synthesis of complete transcripts. However, little is known, in general, about the factors involved in relieving transcriptional attenuation, or specifically how ERα coordinates such factors to promote transcriptional elongation. Using cyclin dependent kinase 9 (CDK9) inhibitors, reporter gene assays and measurements of total and intronic MYB transcription, we show that functionally active CDK9 is required for estrogen-dependent transcriptional elongation. We further show by ChIP and co-immunoprecipitation studies that the P-TEFb complex (CDK9/CyclinT1) is recruited to the attenuation region by ligand-bound ERα, resulting in increased RNA polymerase II Ser-2 phosphorylation. These data provide new insights into MYB regulation, and given the critical roles of MYB in tumorigenesis, suggest targeting MYB elongation as potential therapeutic strategy.
authors.affiliation: University of Queensland Diamantina Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Partha
authors.initials: P
authors.lastname: Mitra
authors.forename: Lloyd A
authors.initials: LA
authors.lastname: Pereira
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drabsch
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D020570:Genes, myb; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012319:RNA Polymerase II / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004958:Estradiol; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II