Thyroid Hormone Receptor Interacting Protein 3 (Trip3) Is a Novel Coactivator of Hepatocyte Nuclear Factor-4α
- Hiromi Iwahashi1,
- Kazuya Yamagata1,
- Issei Yoshiuchi1,
- Jungo Terasaki2,
- Qin Yang1,
- Kenji Fukui1,
- Arisa Ihara1,
- Qian Zhu1,
- Takeshi Asakura1,
- Yang Cao1,
- Akihisa Imagawa1,
- Mitsuyoshi Namba3,
- Toshiaki Hanafusa2,
- Jun-ichiro Miyagawa1 and
- Yuji Matsuzawa1
- 1Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
- 2First Department of Internal Medicine, Osaka Medical College, Osaka, Japan
- 3Second Department of Internal Medicine, Hyogo Medical College of Medicine, Hyogo, Japan
Abstract
Mutations of the hepatocyte nuclear factor-4α (HNF-4α) 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-4α, which is a transcription factor expressed in pancreatic β-cells, plays an important role in regulating the expression of genes involved in glucose metabolism. Thus, cofactors that interact with HNF-4α and modify its transcriptional activity might also play an important role in regulating the metabolic pathways in pancreatic β-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-4α, 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-4α in COS-7 cells and MIN6 cells. These results suggest that Trip3 is a coactivator of HNF-4α. 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-4α.
Footnotes
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Address correspondence and reprint requests to Dr. Kazuya Yamagata, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: kazu{at}imed2.med.osaka-u.ac.jp.
Received for publication 8 August 2001 and accepted in revised form 10 December 2001.
CPRG, chlorophenol red-β-d-galactopyranoside; GST, glutathione S-transferase; HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of the young; SHP, small heterodimer partner; SRC, steroid receptor coactivator; Trip3, thyroid hormone receptor interacting protein 3.
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