title: Sentrin/SUMO specific proteases as novel tissue-selective modulators of vitamin D receptor-mediated signaling.
abstract: Vitamin D receptor (VDR) is a substrate for modification with small ubiquitin-like modifier (SUMO). To further assess the role of reversible SUMOylation within the vitamin D hormonal response, we evaluated the effects of sentrin/SUMO-specific proteases (SENPs) that can function to remove small ubiquitin-like modifier (SUMO) from target proteins upon the activities of VDR and related receptors. We report that SENP1 and SENP2 strikingly potentiate ligand-mediated transactivation of VDR and also its heterodimeric partner, retinoid X receptor (RXRα) with depletion of cellular SENP1 significantly diminishing the hormonal responsiveness of the endogenous vitamin D target gene CYP24A1. We find that SENP-directed modulation of VDR activity is cell line-dependent, achieving potent modulatory effects in Caco-2 and HEK-293 cells, while in MCF-7 cells the vitamin D signal is unaffected by any tested SENP. In support of their function as novel modulators of the vitamin D hormonal pathway we demonstrate that both SENP1 and SENP2 can interact with VDR and reverse its modification with SUMO2. In a preliminary analysis we identify lysine 91, a residue known to be critical for formation and DNA binding of the VDR-RXR heterodimer, as a minor SUMO acceptor site within VDR. In combination, our results support a repressor function for SUMOylation of VDR and reveal SENPs as a novel class of VDR/RXR co-regulatory protein that significantly modulate the vitamin D response and which could also have important impact upon the functionality of both RXR-containing homo and heterodimers.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Sarita
authors.initials: S
authors.lastname: Jena
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Declan
authors.initials: D
authors.lastname: Doherty
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Jaganathan
authors.initials: J
authors.lastname: Ventakesh
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schimdt
authors.affiliation: Divison of Mathematical and Natural Sciences, Arizona State University at the West Campus, Glendale, Arizona, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Furmick
authors.affiliation: Divison of Mathematical and Natural Sciences, Arizona State University at the West Campus, Glendale, Arizona, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: Widener
authors.affiliation: Divison of Mathematical and Natural Sciences, Arizona State University at the West Campus, Glendale, Arizona, United States of America.
authors.forename: Jana
authors.initials: J
authors.lastname: Lemau
authors.affiliation: Divison of Mathematical and Natural Sciences, Arizona State University at the West Campus, Glendale, Arizona, United States of America.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D003412:Cricetulus; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C579457:VDR protein, human; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human