title: Effect of mutations in HNF-1alpha and HNF-1beta on the transcriptional regulation of human sucrase-isomaltase in Caco-2 cells.
abstract: Mutations in transcription factors hepatocyte nuclear factors (HNF)-1alpha and HNF-1beta cause maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. HNF-1alpha and HNF-1beta mutations are well studied in some tissues, but the mechanism by which HNF-1alpha and HNF-1beta mutations affect sucrase-isomaltase (SI) transcription in the small intestine is unclear. We studied the effects of 13 HNF-1alpha mutants and 2 HNF-1beta mutants on human SI gene transcription, which were identified in subjects with MODY3 and MODY5, respectively. Transactivation activity of 11 HNF-1alpha and 2 HNF-1beta mutants was significantly lower than that of wild (wt)-HNF-1alpha and wt-HNF-1beta. Furthermore, in co-expression studies with mutant (mu)-HNF-1alpha/ wt-HNF-1beta and wt-HNF-1alpha/mu-HNF-1beta, the combination of mu-HNF-1alpha (P379fsdelCT and T539fsdelC)/wt-HNF-1beta impaired SI transcription, but the others were not remarkably different from wt-HNF-1alpha/wt-HNF-1beta. Although wt-HNF-1beta inhibited the transactivation activity of wt-HNF-1alpha on SI transcription, the inhibitory effect was reduced by 2 HNF-1beta mutants. These results suggest that SI transcription might tend to be unchanged or lower in MODY3, while occurring more in MODY5.
authors.affiliation: Laboratory of Neurochemistry, Kyoto University Graduate School of Human and Environmental Studies, Kyoto, Japan.
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
authors.forename: Naoko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: Norihiko
authors.initials: N
authors.lastname: Aoki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ishihara
authors.forename: Kinsuke
authors.initials: K
authors.lastname: Tsuda
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000145:classification / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D013394:Sucrase-Isomaltase Complex / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D013394:Sucrase-Isomaltase Complex