Abstract
Although the HNF4 α protein is known to function as a dimer and Q268X heterozygotes carrying mutations in its allele cause MODY1, it is still unclear whether Q268X and wild type HNF4 α can dimerize, and what causes such a distinct phenotype. We visualized the practical and mutual interactions of HNF4 α and Q268X HNF4 α using Fluorescence Resonance Energy Transfer (FRET). A transition in cellular localization was seen in Q268X-HNF4 α complexes from the nucleoplasm to the nucleolus, where wild type HNF4α is normally localized in COS7 and CHO cells. Furthermore, FRET microscopy showed that Q268X-HNF4 α bound to wild type HNF4α and accumulated in the nucleolus. SHP, which is a repressor of HNF4 α, also bound to Q268X and translocated to the nucleolus. The cellular localization of a deletion mutant of HNF4 α showed that the site contributing to nucleolar accumulation is P333 to I338. Some proteins displayed an altered cellular function after localization to the nucleolus. According to these results, transfer to the nucleolus of the heterodimer Q268X-HNF4 α must affect the function of HNF4 α. Consequently, this study showed that Q268X-HNF4 α dimerizes with wild type HNF4 α and also binds with the repressor and changes its localization to the nucleolus. These effects, together with transcription function, may lead to the distinct phenotype of MODY. [J Physiol Sci. 2006;56 Suppl:S110]
