Rescue of MODY-1 by agonist ligands of hepatocyte nuclear factor-4alpha.

abstract

• Missense mutations of the ligand binding domain of hepatocyte nuclear factor (HNF)-4alpha result in maturity onset diabetes of the young (MODY)-1. We show here that MODY-1 as well as Gln-185 missense mutants of the ligand binding domain of HNF-4alpha fail to transactivate transcription of HNF-4alpha-responsive genes. Defective transactivation by these mutants is accounted for by their reduced binding affinities for fatty acyl agonist ligands of HNF-4alpha. These mutants may be rescued by exogenous fatty acid agonist ligands of HNF-4alpha, yielding transcriptional activities in the wild type range. The effect of added ligands is synergistic with that of transcriptional coactivators of HNF-4alpha. These findings may indicate the means for treating selected MODY-1 subjects with HNF-4alpha agonist nutrients and drugs.

authors

• Schroeder, Friedhelm

published proceedings

• J Biol Chem

author list (cited authors)

• Hertz, R., Ben-Haim, N., Petrescu, A. D., Kalderon, B., Berman, I., Eldad, N., Schroeder, F., & Bar-Tana, J.

citation count

• 24

complete list of authors

• Hertz, Rachel||Ben-Haim, Nadav||Petrescu, Anca D||Kalderon, Bella||Berman, Inna||Eldad, Naama||Schroeder, Friedhelm||Bar-Tana, Jacob

publication date

• June 2003

publisher

• Elsevier  Publisher

keywords

• Acyl Coenzyme A
• Amino Acid Substitution
• Animals
• Basic Helix-loop-helix Leucine Zipper Transcription Factors
• COS Cells
• Chlorocebus Aethiops
• DNA-Binding Proteins
• Diabetes Mellitus, Type 2
• Genetic Variation
• Hela Cells
• Hepatocyte Nuclear Factor 4
• Humans
• Kinetics
• Ligands
• Mutation, Missense
• Phosphoproteins
• Recombinant Proteins
• Transcription Factors
• Transcriptional Activation
• Transfection
• Tumor Cells, Cultured

Digital Object Identifier (DOI)

• 10.1074/jbc.M212138200

start page

• 22578

end page

• 22585

volume

• 278

issue

• 25

URL

• http://dx.doi.org/10.1074/jbc.m212138200