title: ERRβ splice variants differentially regulate cell cycle progression.
abstract: Orphan receptors comprise nearly half of all members of the nuclear receptor superfamily. Despite having broad structural similarities to the classical estrogen receptors, estrogen-related receptors (ERRs) have their own unique DNA response elements and functions. In this study, we focus on 2 ERRβ splice variants, short form ERRβ (ERRβsf) and ERRβ2, and identify their differing roles in cell cycle regulation. Using DY131 (a synthetic agonist of ERRβ), splice-variant selective shRNA, and exogenous ERRβsf and ERRβ2 cDNAs, we demonstrate the role of ERRβsf in mediating the G1 checkpoint through p21. We also show ERRβsf is required for DY131-induced cellular senescence. A key novel finding of this study is that ERRβ2 can mediate a G2/M arrest in response to DY131. In the absence of ERRβ2, the DY131-induced G2/M arrest is reversed, and this is accompanied by p21 induction and a G1 arrest. This study illustrates novel functions for ERRβ splice variants and provides evidence for splice variant interaction.
authors.affiliation: a Lombardi Comprehensive Cancer Center; the Department of Oncology ; Georgetown University School of Medicine ; Washington , DC USA.
authors.forename: Mary Mazzotta
authors.initials: MM
authors.lastname: Heckler
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Riggins
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D034622:RNA Interference; D012326:RNA Splicing; D034741:RNA, Small Interfering / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C490918:ESRRB protein, human; D006835:Hydrazones; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53
keywords: ERRbeta; ESRRB; alternative splicing; cell cycle; nuclear receptor; p53; senescence