title: Thyroid hormone receptor interacting protein 3 (trip3) is a novel coactivator of hepatocyte nuclear factor-4alpha.
abstract: Mutations of the hepatocyte nuclear factor-4alpha (HNF-4alpha) gene are associated with a subtype of maturity-onset diabetes of the young (MODY1) that is characterized by impaired insulin secretion in response to a glucose load. HNF-4alpha, which is a transcription factor expressed in pancreatic beta-cells, plays an important role in regulating the expression of genes involved in glucose metabolism. Thus, cofactors that interact with HNF-4alpha and modify its transcriptional activity might also play an important role in regulating the metabolic pathways in pancreatic beta-cells, and the genes of such cofactors are plausible candidate genes for MODY. In the present study, we showed, using a yeast two-hybrid screening assay, that thyroid hormone receptor interacting protein 3 (Trip3) interacted with HNF-4alpha, and their interaction was confirmed by the glutathione S-transferase pull-down assay. Human Trip3 cDNA contained an open reading frame for a protein of 155 amino acids, and the gene was expressed in both pancreatic islets and MIN6 cells. Cotransfection experiments indicated that Trip3 could enhance (two- to threefold) the transcription activity of HNF-4alpha in COS-7 cells and MIN6 cells. These results suggest that Trip3 is a coactivator of HNF-4alpha. Mutation screening revealed that variation of the Trip3 gene is not a common cause of MODY/early-onset type 2 diabetes in Japanese individuals. Trip3 may play an important role in glucose metabolism by regulating the transcription activity of HNF-4alpha.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwahashi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
authors.forename: Issei
authors.initials: I
authors.lastname: Yoshiuchi
authors.forename: Jungo
authors.initials: J
authors.lastname: Terasaki
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukui
authors.forename: Arisa
authors.initials: A
authors.lastname: Ihara
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Asakura
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Akihisa
authors.initials: A
authors.lastname: Imagawa
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Namba
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Miyagawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors