title: Insulin regulates menin expression, cytoplasmic localization, and interaction with FOXO1.
abstract: Menin is the ubiquitously expressed nuclear protein product of the MEN1 gene, which interacts with PKB/Akt in the cytoplasm to inhibit its activity. This study describes a novel insulin-dependent mechanism of menin regulation and interaction with other metabolic proteins. We show that insulin downregulated menin in a time-dependent manner via the human insulin receptor. Inhibition analysis indicated a critical role for the protein kinase Akt in regulation of menin expression and localization. Insulin-mediated decrease in menin expression was abrogated by the PI3K/Akt inhibitor LY-294002 at early time points, from 2 to 7 h. Furthermore, exposure to insulin resulted in the cytoplasmic localization of menin and increased interaction with FOXO1. Fasting followed by refeeding modulates serum insulin levels, which corresponded to an increase in menin interaction with FOXO1 in the liver. Liver-specific hemizygous deletion of menin resulted in increased expression of FOXO1 target genes, namely IGFBP-1, PGC-1α, insulin receptor, Akt, and G-6-Pase. This study provides evidence that menin expression and localization are regulated by insulin signaling and that this regulation triggers an increase in its interaction with FOXO1 via Akt with metabolic consequences.
authors.affiliation: College of Medicine, Univ. of Toledo, Health Science Campus, OH, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Wuescher
authors.forename: Kristine
authors.initials: K
authors.lastname: Angevine
authors.forename: Terry
authors.initials: T
authors.lastname: Hinds
authors.forename: Sadeesh
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Edith J
authors.initials: EJ
authors.lastname: Mensah-Osman
mesh_terms: D000818:Animals; D002458:Cell Fractionation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011972:Receptor, Insulin