title: The Ddx5 and Ddx17 RNA helicases are cornerstones in the complex regulatory array of steroid hormone-signaling pathways.
abstract: Estrogen and androgen receptors (ER and AR) play key roles in breast and prostate cancers, respectively, where they regulate the transcription of large arrays of genes. The activities of ER and AR are controlled by large networks of protein kinases and transcriptional coregulators, including Ddx5 and its highly related paralog Ddx17. The Ddx5 and Ddx17 RNA helicases are also splicing regulators. Here, we report that Ddx5 and Ddx17 are master regulators of the estrogen- and androgen-signaling pathways by controlling transcription and splicing both upstream and downstream of the receptors. First, Ddx5 and Ddx17 are required downstream of ER and AR for the transcriptional and splicing regulation of a large number of steroid hormone target genes. Second, Ddx5 and Ddx17 act upstream of ER and AR by controlling the expression, at the splicing level, of several key regulators of ER and AR activities. Of particular interest, we demonstrate that Ddx5 and Ddx17 control alternative splicing of the GSK3β kinase, which impacts on both ER and AR protein stability. We also provide a freely available online resource which gives information regarding splicing variants of genes involved in the estrogen- and androgen-signaling pathways.
authors.affiliation: Université de Paris Diderot-Paris 7, F-75013 Paris, France, Inserm U1052, F-69008 Lyon, France, CNRS UMR5286, F-69008 Lyon, France, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France and Université de Lyon 1, F-69100 Villeurbanne, France.
authors.forename: Samaan
authors.initials: S
authors.lastname: Samaan
authors.forename: Léon-Charles
authors.initials: LC
authors.lastname: Tranchevent
authors.forename: Etienne
authors.initials: E
authors.lastname: Dardenne
authors.forename: Micaela
authors.initials: M
authors.lastname: Polay Espinoza
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zonta
authors.forename: Sophie
authors.initials: S
authors.lastname: Germann
authors.forename: Lise
authors.initials: L
authors.lastname: Gratadou
authors.forename: Martin
authors.initials: M
authors.lastname: Dutertre
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
mesh_terms: D017398:Alternative Splicing; D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D061986:MCF-7 Cells; D055550:Protein Stability; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000728:Androgens; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004958:Estradiol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C102004:DDX17 protein, human; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases