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Regulation of a Transcription Factor Network Required for Differentiation and Metabolism

Science  31 Jul 1998:
Vol. 281, Issue 5377, pp. 692-695
DOI: 10.1126/science.281.5377.692

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Abstract

Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. Mutations in HNF-1αand HNF-4α genes impair insulin secretion and cause type 2 diabetes. Regulation of HNF-4/HNF-1 expression byHNF-3α and HNF-3β was studied in embryoid bodies in which one or both HNF-3α or HNF-3βalleles were inactivated. HNF-3β positively regulated the expression of HNF-4α/HNF-1α and their downstream targets, implicating a role in diabetes. HNF-3β was also necessary for expression of HNF-3α. In contrast, HNF-3α acts as a negative regulator of HNF-4α/HNF-1α demonstrating thatHNF-3α and HNF-3β have antagonistic transcriptional regulatory functions in vivo. HNF-3α does not appear to act as a classic biochemical repressor but rather exerts its negative effect by competing for HNF-3 binding sites with the more efficient activatorHNF-3β. In addition, the HNF-3α/HNF-3β ratio is modulated by the presence of insulin, providing evidence that the HNF network may have important roles in mediating the action of insulin.

  • * Present address: Department of Cell Biology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

  • To whom correspondence should be addressed. E-mail: stoffel{at}rockvax.rockefeller.edu

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