title: Repression of CMIP transcription by WT1 is relevant to podocyte health.
abstract: The WT1 (Wilm's tumor suppressor) gene is expressed throughout life in podocytes and is essential for the functional integrity of the glomerular filtration barrier. We have previously shown that CMIP (C-Maf inducing protein) is overproduced in podocyte diseases and alters intracellular signaling. Here we isolated the proximal region of the human CMIP promoter and showed by chromatin immunoprecipitation assays and electrophoretic-mobility shift that Wilm's tumor protein (WT1) bound to 2 WT1 response elements, located at positions -290/-274 and -57/-41 relative to transcription start site. Unlike the human CMIP gene, only one Wt1 response element was identified in the mouse Cmip proximal promoter located at position -217/-206. Luciferase reporter assays indicated that WT1 dose-dependently inhibited the transcriptional induction of the CMIP promoter. Transfection of decoy oligonucleotides mimicking the WT1 response elements prevented the inhibition of WT1 on CMIP promoter activity. Furthermore, WT1 silencing promoted Cmip expression. In line with these findings, the abundance of Cmip was early and significantly increased at the transcript and protein level in podocytes displaying a primary defect in Wt1, including Denys-Drash syndrome and Frasier syndrome. Thus, WT1 is a major repressor of the CMIP gene in physiological situations, while conditional deletion of CMIP in the developing kidney did not affect the development of mature glomeruli.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Anissa
authors.initials: A
authors.lastname: Moktefi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Shao-Yu
authors.initials: SY
authors.lastname: Zhang
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Vachin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Ory
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Henique
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de Néphrologie, Créteil, France; Institut Francilien de Recherche en Néphrologie et Transplantation, Henri Mondor Hospital, Créteil, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Audard
authors.affiliation: Centre Chirurgical Marie Lannelongue, Institut National de la Santé et de la Recherche Médicale, Le Plessis Robinson, France; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rucker-Martin
authors.affiliation: Centre Chirurgical Marie Lannelongue, Institut National de la Santé et de la Recherche Médicale, Le Plessis Robinson, France; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Gouadon
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Michael
authors.initials: M
authors.lastname: Eccles
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche, University of Nice/Sophia Antipolis, Nice, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.affiliation: APHP, Centre de Référence des Maladies Rénales Héréditaires de l'enfant et de l'adulte et Service de Néphrologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Ollero
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de Néphrologie, Créteil, France; Institut Francilien de Recherche en Néphrologie et Transplantation, Henri Mondor Hospital, Créteil, France. Electronic address: dil.sahali@inserm.fr.
authors.forename: Djillali
authors.initials: D
authors.lastname: Sahali
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
authors.forename: Andre
authors.initials: A
authors.lastname: Pawlak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D030321:Denys-Drash Syndrome / Q000378:metabolism; D005260:Female; D052159:Frasier Syndrome / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000196:embryology; D008297:Male; D051379:Mice; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025721:WT1 Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C540426:CMIP protein, human; C551587:Cmip protein, mouse; D025721:WT1 Proteins; C583751:WT1 protein, human
keywords: cell signaling; gene expression; kidney development; nephrotic syndrome; podocyte; transcription regulation