title: AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells.
abstract: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas through unknown molecular mechanisms. The best-known interacting partner of AIP is the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the effects of xenobiotics implicated in carcinogenesis. As 75% of AIP mutations disrupt the physical and/or functional interaction with AhR, we postulated that the tumorigenic potential of AIP mutations might result from altered AhR signaling. We evaluated the impact of AIP mutations on the AhR signaling pathway, first in fibroblasts from AIP-mutated patients with pituitary adenomas, by comparison with fibroblasts from healthy subjects, then in transfected pituitary GH3 cells. The AIP protein level in mutated fibroblasts was about half of that in cells from healthy subjects, but AhR expression was unaffected. Gene expression analyses showed significant modifications in the expression of the AhR target genes CYP1B1 and AHRR in AIP-mutated fibroblasts, both before and after stimulation with the endogenous AhR ligand kynurenine. Kynurenine increased Cyp1b1 expression to a greater extent in GH3 cells overexpressing wild type compared with cells expressing mutant AIP Knockdown of endogenous Aip in these cells attenuated Cyp1b1 induction by the AhR ligand. Both mutant AIP expression and knockdown of endogenous Aip affected the kynurenine-dependent GH secretion of GH3 cells. This study of human fibroblasts bearing endogenous heterozygous AIP mutations and transfected pituitary GH3 cells shows that AIP mutations affect the AIP protein level and alter AhR transcriptional activity in a gene- and tissue-dependent manner.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Lecoq
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Mirella
authors.initials: M
authors.lastname: Hage
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bouligand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.affiliation: Assistance Publique-Hôpitaux de ParisService de Biochimie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Boutron
authors.affiliation: Inserm U894Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Zizzari
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin-Bicêtre, France peter.kamenicky@bct.aphp.fr.
authors.forename: Peter
authors.initials: P
authors.lastname: Kamenický
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002460:Cell Line; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D065633:Cytochrome P-450 CYP1B1; D047908:Intracellular Signaling Peptides and Proteins; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C492162:AHRR protein, human; C103265:aryl hydrocarbon receptor-interacting protein; C585496:CYP1B1 protein, human
keywords: AIP; AhR; pituitary adenomas