title: The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity.
abstract: Hypoxia-inducible transcription factor-1 (HIF-1) plays a decisive role in cell survival and adaptation to hypoxic stress by controlling the expression of genes involved in oxygen homeostasis. HIF-1 activity is fine-tuned through specific post-translational modifications of its essential HIF-1α subunit. Among these modifications, phosphorylation is important for HIF-1 transcriptional activity. Studies have shown that the mitogen-activated protein kinases, p42/p44 MAPKs, directly phosphorylate HIF-1α and increase HIF-1-mediated transcription. Pin1, a peptidyl-prolyl cis/trans isomerase, targets a number of proteins containing a phosphorylated Ser/Thr-Pro motif. Pin1 isomerization causes a change in target protein conformation which can modify their activity. Here, we identify Pin1 as an important HIF-1α partner. Immunoprecipitation and pull-down studies show that Pin1 interacts with HIF-1α. We demonstrate that the interaction between Pin1 and HIF-1α is regulated through p42/p44 MAPK pathway activation. By performing proteolysis studies, our results indicate that Pin1 catalytic activity generates a conformational change in HIF-1α. Finally, our work shows that Pin1 is required for gene-specific HIF-1 transcriptional activity. Our results indicate that the prolyl isomerase Pin1 regulates HIF-1 transcriptional activity by interacting with HIF-1α and promoting conformational changes in a p42/p44 MAPK phosphorylation-dependent manner.
authors.affiliation: Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada.
authors.forename: Maroua
authors.initials: M
authors.lastname: Jalouli
authors.affiliation: Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada.
authors.forename: Marc-André C
authors.initials: MA
authors.lastname: Déry
authors.affiliation: Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada.
authors.forename: Véronique N
authors.initials: VN
authors.lastname: Lafleur
authors.affiliation: Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lamalice
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.affiliation: Centre de recherche du CHU de Québec, L'Hôtel-Dieu de Québec, Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC G1R 3S3, Canada. Electronic address: darren.richard@crhdq.ulaval.ca.
authors.forename: Darren E
authors.initials: DE
authors.lastname: Richard
mesh_terms: D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: HIF-1; Hypoxia; Isomerase; Phosphorylation; Pin1; VEGF