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Science 31 July 1998:
Vol. 281. no. 5377, pp. 692 - 695
DOI: 10.1126/science.281.5377.692
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Reports

Regulation of a Transcription Factor Network Required for Differentiation and Metabolism

Stephen A. Duncan, * M. Angeles Navas, Daniel Dufort, Janet Rossant, Markus Stoffel dagger

Hepatocyte nuclear factors (HNFs) are a heterogeneous class of evolutionarily conserved transcription factors that are required for cellular differentiation and metabolism. Mutations in HNF-1alpha and HNF-4alpha genes impair insulin secretion and cause type 2 diabetes. Regulation of HNF-4/HNF-1 expression by HNF-3alpha and HNF-3beta was studied in embryoid bodies in which one or both HNF-3alpha or HNF-3beta alleles were inactivated. HNF-3beta positively regulated the expression of HNF-4alpha /HNF-1alpha and their downstream targets, implicating a role in diabetes. HNF-3beta was also necessary for expression of HNF-3alpha . In contrast, HNF-3alpha acts as a negative regulator of HNF-4alpha /HNF-1alpha demonstrating that HNF-3alpha and HNF-3beta have antagonistic transcriptional regulatory functions in vivo. HNF-3alpha 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 activator HNF-3beta . In addition, the HNF-3alpha /HNF-3beta ratio is modulated by the presence of insulin, providing evidence that the HNF network may have important roles in mediating the action of insulin.

S. A. Duncan, M. A. Navas, M. Stoffel, Laboratories of Molecular Cell Biology and Metabolic Diseases, Rockefeller University, New York, NY 10021, USA. D. Dufort and J. Rossant, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
*   Present address: Department of Cell Biology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

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

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Identification of Transacting Factors Responsible for the Tissue-specific Expression of Human Glucose Transporter Type 2 Isoform Gene. COOPERATIVE ROLE OF HEPATOCYTE NUCLEAR FACTORS 1alpha AND 3beta.
J.-Y. Cha, H.-i. Kim, K.-S. Kim, M.-W. Hur, and Y.-h. Ahn (2000)
J. Biol. Chem. 275, 18358-18365
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Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro.
M. J. Shamblott, J. Axelman, J. W. Littlefield, P. D. Blumenthal, G. R. Huggins, Y. Cui, L. Cheng, and J. D. Gearhart (2001)
PNAS 98, 113-118
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