title: Foxa2, a novel protein partner of the tumour suppressor menin, is deregulated in mouse and human MEN1 glucagonomas.
abstract: Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon. However, its expression and biological role in adult pancreatic α-cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α-cell-specific Men1 mutant mice, at both the transcriptional level and the protein level. More importantly, immunostaining analyses showed its prominent nuclear accumulation, specifically in α-cells, at a very early stage after Men1 disruption. Similar nuclear FOXA2 expression was also detected in a substantial proportion (12/19) of human multiple endocrine neoplasia type 1 (MEN1) glucagonomas. Interestingly, our data revealed an interaction between Foxa2 and menin encoded by the Men1 gene. Furthermore, using several approaches, we demonstrated the relevance of this interaction in the regulation of two tested Foxa2 target genes, including the autoregulation of the Foxa2 promoter by Foxa2 itself. The current study establishes menin, a novel protein partner of Foxa2, as a regulator of Foxa2, the biological functions of which extend beyond the pancreatic endocrine cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bonnavion
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Teinturier
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Samuele
authors.initials: S
authors.lastname: Gherardi
authors.affiliation: Institut de Pathologie, CHRU de Lille, Lille, France.|Department of Endocrinology and Metabolism, Univ. Lille 2, INSERM UMR 1190, Lille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Run
authors.initials: R
authors.lastname: Yu
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Cordier-Bussat
authors.affiliation: The E-Institute of Shanghai, Sino-French Life Science and Genomic Centre, Ruijin Hospital, Shanghai, PR China.|Shanghai Clinical Centre for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao-Tong University, Shanghai, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Du
authors.affiliation: Department of Endocrinology and Metabolism, Univ. Lille 2, INSERM UMR 1190, Lille, France.|CHRU Lille, Endocrine Surgery, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Department of Endocrinology and Metabolism, Univ. Lille 2, INSERM UMR 1190, Lille, France.|CHRU Lille, Endocrinology, Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.|The E-Institute of Shanghai, Sino-French Life Science and Genomic Centre, Ruijin Hospital, Shanghai, PR China.|Shanghai Clinical Centre for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao-Tong University, Shanghai, PR China.
authors.forename: Jieli
authors.initials: J
authors.lastname: Lu
authors.affiliation: INSERM U1052, Lyon, France.|CNRS UMR5286, Lyon, France.|Université de Lyon, Lyon, France.|The E-Institute of Shanghai, Sino-French Life Science and Genomic Centre, Ruijin Hospital, Shanghai, PR China.
authors.forename: Chang Xian
authors.identifier: 0000-0002-5443-8951
authors.initials: CX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D005935:Glucagonoma / Q000235:genetics / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008822:Mice, Transgenic; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C496502:FOXA2 protein, human; C496503:Foxa2 protein, mouse; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Foxa2; functional interaction; glucagonoma; menin; pancreatic α-cells