The G115S mutation associated with maturity-onset diabetes of the young impairs hepatocyte nuclear factor 4alpha activities and introduces a PKA phosphorylation site in its DNA-binding domain

The Biochemical Journal
Bénédicte OxombreB Laine

Abstract

HNF4alpha (hepatocyte nuclear factor 4alpha) belongs to a complex transcription factor network that is crucial for the function of hepatocytes and pancreatic beta-cells. In these cells, it activates the expression of a very large number of genes, including genes involved in the transport and metabolism of glucose and lipids. Mutations in the HNF4alpha gene correlate with MODY1 (maturity-onset diabetes of the young 1), a form of type II diabetes characterized by an impaired glucose-induced insulin secretion. The MODY1 G115S (Gly115-->Ser) HNF4alpha mutation is located in the DNA-binding domain of this nuclear receptor. We show here that the G115S mutation failed to affect HNF4alpha-mediated transcription on apolipoprotein promoters in HepG2 cells. Conversely, in pancreatic beta-cell lines, this mutation resulted in strong impairments of HNF4alpha transcriptional activity on the promoters of LPK (liver pyruvate kinase) and HNF1alpha, with this transcription factor playing a key role in endocrine pancreas. We show as well that the G115S mutation creates a PKA (protein kinase A) phosphorylation site, and that PKA-mediated phosphorylation results in a decreased transcriptional activity of the mutant. Moreover, the G115E (Gly115-->Gl...Continue Reading

References

Apr 1, 1997·Archives of Biochemistry and Biophysics·G JiangF M Sladek
May 29, 1998·The Journal of Clinical Investigation·M PontoglioK S Polonsky
Jun 17, 1998·Genes & Development·J C BlancoK Ozato
Aug 12, 1998·Journal of Molecular Biology·S M HolmbeckP E Wright
May 5, 1999·Diabetic Medicine : a Journal of the British Diabetic Association·M T MaleckiA S Krolewski
Sep 29, 2001·The New England Journal of Medicine·S S FajansK S Polonsky
Oct 2, 2001·Current Opinion in Chemical Biology·D T McLachlin, B T Chait
Dec 6, 2001·Proceedings of the National Academy of Sciences of the United States of America·D Q Shih, M Stoffel
Mar 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·David Q ShihMarkus Stoffel
May 8, 2002·The Journal of Biological Chemistry·Reut Bartoov-ShifmanMichael D Walker
Aug 24, 2002·The Journal of Biological Chemistry·Sirano Dhe-PaganonSteven E Shoelson
Dec 18, 2002·The Journal of Biological Chemistry·Tomas DobranskyR Jane Rylett
Mar 26, 2003·Proceedings of the National Academy of Sciences of the United States of America·James RheeBruce M Spiegelman
Feb 28, 2004·Science·Duncan T OdomRichard A Young

❮ Previous
Next ❯

Citations

May 30, 2008·Frontiers in Bioscience : a Journal and Virtual Library·Krishna KadaveruMartin R Schiller
Nov 23, 2006·Diabetic Medicine : a Journal of the British Diabetic Association·K Navalón-GarcíaA Miliar-García
May 23, 2014·International Journal of Environmental Health Research·Olga Lidia Tavares-SanchezMaria Isabel Estrada
Oct 15, 2005·American Journal of Physiology. Gastrointestinal and Liver Physiology·Christopher W RowleyTheodore C Simon
Jun 19, 2007·Journal of Molecular Biology·Zhongyan Wang, Peter A Burke

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adrenocortical Carcinoma

Hepatocellular carcinoma is the most common type of primary liver cancer and frequently occurs in individuals with chronic liver diseases like cirrhosis. Here is the latest research.

Carcinoma, Hepatocellular

Hepatocellular Carcinoma is a malignant cancer in liver epithelial cells. Discover the latest research on Hepatocellular Carcinoma here.