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Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals
Author(s) -
Duran Joan,
Obach Mercè,
NavarroSabate Aurea,
Manzano Anna,
Gómez Marta,
Rosa Jose L.,
Ventura Francesc,
Perales Jose C.,
Bartrons Ramon
Publication year - 2009
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.07161.x
Subject(s) - streptozotocin , biology , pi3k/akt/mtor pathway , kinase , glycolysis , downregulation and upregulation , protein kinase b , hepatocyte , microbiology and biotechnology , chemistry , phosphorylation , endocrinology , signal transduction , biochemistry , gene , diabetes mellitus , metabolism , in vitro
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.