| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
and HNF-1 revealed by mutations that cause maturity onset diabetes of the young
1 Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA
2 Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA; Division of Biology and Biomedical Sciences, Washington University School of Medicine, Saint Louis, Missouri, USA
* To whom correspondence should be addressed. E-mail: simon_t{at}kids.wustsl.edu.
HNF-4
and HNF-1 are key endodermal transcriptional regulators that physically and functionally interact. HNF-4 and HNF-1 cooperatively activate genes with binding sites for both factors, while suppressive interactions occur at regulatory sequences with a binding site for only one factor. The liver fatty acid binding protein gene (Fabp1) has binding sites for both factors, and chromatin precipitation assays were utilized to demonstrate that HNF-4 increased HNF-1 Fabp1 promoter occupancy during cooperative transcriptional activation. The HNF4 P2 promoter contains an HNF-1 but not HNF-4 binding site, and HNF-4 suppressed HNF-1 HNF4 P2 activation and decreased promoter HNF-1 occupancy. The APOC3 promoter contains an HNF-4 but not HNF-1 binding site, and HNF-1 suppressed HNF-4 APOC3 activation and decreased HNF-4 promoter occupancy. Maturity onset diabetes of the young (MODY) as well as defects in hepatic lipid metabolism result from mutations in either HNF-4 or HNF-1. We found that MODY missense mutant R127W HNF-4 retained wild-type individual Fabp1 activation and bound to HNF-1 better than wild-type HNF-4, yet did not cooperate with HNF-1 or increase HNF-1 Fabp1 promoter occupancy. R127W was also defective both in suppressing HNF-1 activation of HNF4 P2 and decreasing HNF-1 promoter occupancy. An HNF-1 R131Q MODY mutant also retained wild-type Fabp1 activation and bound to HNF-4 as well as wild-type, but was defective both in suppression of HNF-4 APOC3 activation and decreasing HNF-4 promoter occupancy. These results suggest HNF-1:HNF-4 functional interactions are accomplished by regulating factor promoter occupancy, and that defective factor-factor interactions may contribute to the MODY phenotype.
This article has been cited by other articles:
|
|
 |
|
  A. Perilhou, C. Tourrel-Cuzin, P. Zhang, I. Kharroubi, H. Wang, V. Fauveau, D. K. Scott, C. B. Wollheim, and M. Vasseur-Cognet The MODY1 Gene for Hepatocyte Nuclear Factor 4{alpha} and a Feedback Loop Control COUP-TFII Expression in Pancreatic Beta Cells Mol. Cell. Biol., July 15, 2008; 28(14): 4588 - 4597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Dietrich, I. V. Martin, A. C. Porn, S. Voigt, C. Gartung, C. Trautwein, and A. Geier Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4{alpha} and PGC1{alpha} Am J Physiol Gastrointest Liver Physiol, September 1, 2007; 293(3): G585 - G590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Leng, S. Lu, Y. Yao, Z. Kan, G. S. Morris, B. R. Stair, M. A. Cherny, and D. D. Black Hepatocyte nuclear factor-4 mediates apolipoprotein A-IV transcriptional regulation by fatty acid in newborn swine enterocytes Am J Physiol Gastrointest Liver Physiol, August 1, 2007; 293(2): G475 - G483. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
