title: Pin1 promotes GR transactivation by enhancing recruitment to target genes.
abstract: The glucocorticoid receptor (GR) is a ligand activated transcription factor, serving to regulate both energy metabolism and immune functions. Factors that influence cellular sensitivity to glucocorticoids (GC) are therefore of great interest. The N-terminal of the GR contains numerous potential proline-directed phosphorylation sites, some of which can regulate GR transactivation. Unrestricted proline isomerisation can be inhibited by adjacent serine phosphorylation and requires a prolyl isomerise, Pin1. Pin1 therefore determines the functional outcome of proline-directed kinases acting on the GR, as cis/trans isomers are distinct pools with different interacting proteins. We show that Pin1 mediates GR transactivation, but not GR trans-repression. Two N-terminal GR serines, S203 and S211, are targets for Pin1 potentiation of GR transactivation, establishing a direct link between Pin1 and the GR. We also demonstrate GC-activated co-recruitment of GR and Pin1 to the GILZ gene promoter. The Pin1 effect required both its WW and catalytic domains, and GR recruitment to its GRE was Pin1-dependent. Therefore, Pin1 is a selective regulator of GR transactivation, acting through N-terminal phospho-serine residues to regulate GR recruitment to its target sites in the genome. As Pin1 is dysregulated in disease states, this interaction may contribute to altered GC action in inflammatory conditions.
authors.affiliation: Centre in Endocrinology and Diabetes, Institute of Human Development, University of Manchester, Manchester, M13 9PT, UK, Respiratory Therapy Area, GSK, Stevenage, SG1 2NY, UK, Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK and Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.
authors.forename: Toryn M
authors.initials: TM
authors.lastname: Poolman
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Farrow
authors.forename: Laura
authors.initials: L
authors.lastname: Matthews
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Loudon
authors.forename: David W
authors.initials: DW
authors.lastname: Ray
mesh_terms: D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D056921:Nuclear Receptor Coactivator 3 / Q000502:physiology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D003907:Dexamethasone; D056921:Nuclear Receptor Coactivator 3; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase