Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals.
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.
Duran
Joan
J
Unitat Bioquímica i Biologia Molecular, Universitat de Barcelona, Spain.
Obach
Mercè
M
Navarro-Sabate
Aurea
A
Manzano
Anna
A
Gómez
Marta
M
Rosa
Jose L
JL
Ventura
Francesc
F
Perales
Jose C
JC
Bartrons
Ramon
R
D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental; D005635:Fructosediphosphates / Q000032:analysis; D006019:Glycolysis; D008099:Liver / Q000201:enzymology*; D051379:Mice; D025481:Phosphofructokinase-2 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation
D005635:Fructosediphosphates; D012333:RNA, Messenger; C027652:fructose 2,6-diphosphate; D025481:Phosphofructokinase-2