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Localization of hepatocyte nuclear factor‐4α in the nucleolus and nucleus is regulated by its C‐terminus
Authors:Makiko Ogata  Takeo Awaji  Naoko Iwasaki  Risa Fujimaki  Miho Takizawa  Kei Maruyama  Graeme I Bell  Yasuhiko Iwamoto  Yasuko Uchigata
Affiliation:1. Department of Medicine III and Diabetes Center, Tokyo Women’s Medical University School of Medicine, Tokyo;2. Department of Pharmacology, Saitama Medical University School of Medicine, Saitama, Japan;3. Department of Medicine and Human Genetics, University of Chicago, Chicago, IL, USA
Abstract:Aims/Introduction: Mutations in hepatocyte nuclear factor‐4α (HNF4α) lead to various diseases, among which C‐terminal deletions of HNF4α are exclusively responsible for maturity onset diabetes of the young 1 (MODY1). MODY is an autosomal dominant disease characterized by a primary defect in insulin response to glucose, suggesting that the C‐terminus of HNF4α is important for pancreatic β‐cell function. To clarify the role of the C‐terminus of HNF4α, changes in cellular localization and the binding ability to its regulator were examined, specifically in the region containing Q268, which deletion causes MODY1. Materials and Methods: Cellular localization of mutant HNF4α were examined in monkey kidney 7 (COS7), Chinese hamster ovary, rat insulinoma and mouse insulinoma cells, and their binding activity to other proteins were examined by fluorescence resonance energy transfer (FRET) in COS7 cells. Results: Although wild‐type HNF4α was localized in the nucleoplasm in transfected cultured cells, Q268X‐HNF4α was located predominantly in the nucleolus. Deletion analysis of the C‐terminus of HNF4α showed that the S337X‐HNF4α mutant, and other mutants with shorter amino acid sequences (S337‐K194), were mostly localized in the nucleolus. HNF4α mutants with amino acid sequences shorter than the W192X‐HNF4α mutant gradually spread to the nucleoplasm in accordance with their lengths. The A250X‐HNF4α mutant was capable of causing the accumulation of HNF4α or the small heterodimer partner (SHP), one of the HNF4α regulators, in the nucleolus. However, the R154X‐HNF4α mutant did not have binding ability to wild‐type HNF4α or SHP, and thus was seen in the nucleus. Conclusions: The C‐terminus sites might play a key role in facilitating the nucleolar and subnucleolar localization of HNF4α. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00210.x, 2012)
Keywords:Fluorescence resonance energy transfer  Hepatocyte nuclear factor‐4α    Nucleolus
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