title: PIAS4 represses vitamin D receptor-mediated signaling and acts as an E3-SUMO ligase towards vitamin D receptor.
abstract: The present study investigated the potential for members of the protein inhibitors of activated STAT (PIAS) family to function as co-regulators of the vitamin D signal pathway. Among the PIAS proteins evaluated, we establish PIAS4 as a potent inhibitor of the transcriptional responses of the CYP3A4 and CYP24A1 target genes to the active hormonal form of vitamin D, a repression that was observed to be dependent upon an intact SUMO-ligase function of PIAS4. We report that PIAS4 represents a direct binding partner for vitamin D receptor (VDR) and also facilitates its modification with SUMO2, a process that preferentially occurs on the apo-form of VDR and which is reversed upon binding of ligand. Our results implicate PIAS4 and the process of SUMOylation as important modulators of VDR-mediated signaling which may both represent flexible mechanistic components as to how vitamin D achieves its pleiotropic effects.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: Sarita
authors.initials: S
authors.lastname: Jena
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Lee
authors.forename: Declan
authors.initials: D
authors.lastname: Doherty
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D018167:Receptors, Calcitriol; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D044767:Ubiquitin-Protein Ligases