Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals

FEBS J. 2009 Aug;276(16):4555-68. doi: 10.1111/j.1742-4658.2009.07161.x. Epub 2009 Jul 18.


The ubiquitous isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (uPFK-2), a product of the Pfkfb3 gene, plays a crucial role in the control of glycolytic flux. In this study, we demonstrate that Pfkfb3 gene expression is increased in streptozotocin-induced diabetic mouse liver. The Pfkfb3/-3566 promoter construct linked to the luciferase reporter gene was delivered to the liver via hydrodynamic gene transfer. This promoter was upregulated in streptozotocin-induced diabetic mouse liver compared with transfected healthy cohorts. In addition, increases were observed in Pfkfb3 mRNA and uPFK-2 protein levels, and intrahepatic fructose-2,6-bisphosphate concentration. During streptozotocin-induced diabetes, phosphorylation of both p38 mitogen-activated protein kinase and Akt was detected, together with the overexpression of the proliferative markers cyclin D and E2F. These findings indicate that uPFK-2 induction is coupled to enhanced hepatocyte proliferation in streptozotocin-induced diabetic mouse liver. Expression decreased when hepatocytes were treated with either rapamycin or LY 294002. This shows that uPFK-2 regulation is phosphoinositide 3-kinase-Akt-mammalian target of rapamycin dependent. These results indicate that fructose-2,6-bisphosphate is essential to the maintenance of the glycolytic flux necessary for providing energy and biosynthetic precursors to dividing cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation*
  • Diabetes Mellitus, Experimental
  • Fructosediphosphates / analysis
  • Glycolysis
  • Liver / enzymology*
  • Mice
  • Phosphofructokinase-2 / genetics*
  • RNA, Messenger / analysis
  • Signal Transduction*
  • Transcription, Genetic*
  • Up-Regulation


  • Fructosediphosphates
  • RNA, Messenger
  • fructose 2,6-diphosphate
  • Phosphofructokinase-2