Abstract
The activation of glycolytic flux is a biochemical characteristic of growing cells. Several reports have demonstrated the role of fructose 2,6-bisphosphate in this process. In this paper we show that the levels of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (6PF2K/Fru-2,6-P2ase) mRNA are modulated in response to serum and growth factors and this effect is due to regulation of its transcription rate. The modulation of the expression of this enzyme by growth factors differs according their mitogenic effect; both lysophosphatidic acid and epidermal growth factor, when added alone, increased the mRNA levels, but endothelin had no effect. Furthermore, cAMP, which acts as an antimitogenic signal in Rat-1 fibroblasts, produced a decrease in 6PF2K/Fru-2, 6-P2ase mRNA and inhibited the effects of lysophosphatidic acid and epidermal growth factor on 6PF2K/Fru-2,6-P2ase expression. PD 098059, a specific inhibitor of the activation of the mitogen-activated protein kinase, was able to prevent the effect of EGF on 6PF2K/Fru-2, 6-P2ase gene expression. These results imply that activation of mitogen-activated protein kinase is required for the stimulation of the transcription of 6PF2K/Fru-2,6-P2ase by EGF.
Highlights
Quiescent cells can be stimulated to recommence DNA synthesis by distinct and interactive signal transduction pathways
The results presented here demonstrate that mitogenactivated protein kinases ERK1 and ERK2 (MAPKs) is involved in the regulation of 6PF2K/Fru-2,6P2ase gene transcription in response to mitogenic signals
lysophosphatidic acid (LPA), and epidermal growth factor (EGF), complete mitogens for Rat-1 fibroblasts [42], were able to increase the mRNA levels of 6PF2K/Fru-2,6P2ase and Fru-2,6-P2 content
Summary
Quiescent cells can be stimulated to recommence DNA synthesis by distinct and interactive signal transduction pathways. The increase in this metabolite has been correlated with an increase in the Vmax of 6-phosphofructo-2-kinase activity (19 –24) This metabolic effect is clear, the mechanism by which it is achieved is not known. A study of the regulation of Fru-2,6-P2 metabolism through different signal transduction pathways has been performed using murine Swiss 3T3 fibroblasts as a model [21]. The aim of this work is to study the signaling pathways that control the transcription of the 6PF2K/Fru-2,6-P2ase gene during cell proliferation For this propose, we have investigated the effect of EGF, lysophosphatidic acid (LPA), endothelin, and cholera toxin (CTx) on 6PF2K/Fru-2,6-P2ase gene expression in Rat-1 fibroblasts and the role of mitogen-activated kinase (MAPK) in this regulation
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