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: Ning Gu, Naoko Suzuki, Jun Takeda, Tetsuya Adachi, Gozoh Tsujimoto, Norihiko Aoki, Akihiko Ishihara, Kinsuke Tsuda, Koichiro Yasuda
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 325 Issue 1 Pg. 308-13 (Dec 03 2004) ISSN: 0006-291X [Print] United States
• PMID: 15522234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• HNF1A protein, human
• HNF1B protein, human
• Hepatocyte Nuclear Factor 1-alpha
• Nuclear Proteins
• Transcription Factors
• Hepatocyte Nuclear Factor 1
• Hepatocyte Nuclear Factor 1-beta
• Sucrase-Isomaltase Complex

Topics

• Animals
• Caco-2 Cells
• DNA-Binding Proteins (genetics, metabolism)
• Diabetes Mellitus, Type 2 (classification, genetics, metabolism)
• Gene Expression Regulation
• Hepatocyte Nuclear Factor 1
• Hepatocyte Nuclear Factor 1-alpha
• Hepatocyte Nuclear Factor 1-beta
• Humans
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Sucrase-Isomaltase Complex (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic