TY - JOUR
T1 - Glucose-6-phosphate mediates activation of the carbohydrate responsive binding protein (ChREBP)
AU - Li, Ming V.
AU - Chen, Weiqin
AU - Harmancey, Romain N.
AU - Nuotio-Antar, Alli M.
AU - Imamura, Minako
AU - Saha, Pradip
AU - Taegtmeyer, Heinrich
AU - Chan, Lawrence
N1 - Funding Information:
This work was supported by NIH Grants DK68037 , HL51586 and HL-037162 , the Diabetes and Endocrinology Research Center ( P30DK079638 ) at Baylor College of Medicine, the Rutherford Chair for Diabetes Research from St. Luke’s Episcopal Hospital, and the T.T. & W.F. Chao Foundation. We thank Dr. Jason Chesney for pIRESneo3-iPFK2.
PY - 2010/5/7
Y1 - 2010/5/7
N2 - Carbohydrate response element binding protein (ChREBP) is a Mondo family transcription factor that activates a number of glycolytic and lipogenic genes in response to glucose stimulation. We have previously reported that high glucose can activate the transcriptional activity of ChREBP independent of the protein phosphatase 2A (PP2A)-mediated increase in nuclear entry and DNA binding. Here, we found that formation of glucose-6-phosphate (G-6-P) is essential for glucose activation of ChREBP. The glucose response of GAL4-ChREBP is attenuated by d-mannoheptulose, a potent hexokinase inhibitor, as well as over-expression of glucose-6-phosphatase (G6Pase); kinetics of activation of GAL4-ChREBP can be modified by exogenously expressed GCK. Further metabolism of G-6-P through the two major glucose metabolic pathways, glycolysis and pentose-phosphate pathway, is not required for activation of ChREBP; over-expression of glucose-6-phosphate dehydrogenase (G6PD) diminishes, whereas RNAi knockdown of the enzyme enhances, the glucose response of GAL4-ChREBP, respectively. Moreover, the glucose analogue 2-deoxyglucose (2-DG), which is phosphorylated by hexokinase, but not further metabolized, effectively upregulates the transcription activity of ChREBP. In addition, over-expression of phosphofructokinase (PFK) 1 and 2, synergistically diminishes the glucose response of GAL4-ChREBP. These multiple lines of evidence support the conclusion that G-6-P mediates the activation of ChREBP.
AB - Carbohydrate response element binding protein (ChREBP) is a Mondo family transcription factor that activates a number of glycolytic and lipogenic genes in response to glucose stimulation. We have previously reported that high glucose can activate the transcriptional activity of ChREBP independent of the protein phosphatase 2A (PP2A)-mediated increase in nuclear entry and DNA binding. Here, we found that formation of glucose-6-phosphate (G-6-P) is essential for glucose activation of ChREBP. The glucose response of GAL4-ChREBP is attenuated by d-mannoheptulose, a potent hexokinase inhibitor, as well as over-expression of glucose-6-phosphatase (G6Pase); kinetics of activation of GAL4-ChREBP can be modified by exogenously expressed GCK. Further metabolism of G-6-P through the two major glucose metabolic pathways, glycolysis and pentose-phosphate pathway, is not required for activation of ChREBP; over-expression of glucose-6-phosphate dehydrogenase (G6PD) diminishes, whereas RNAi knockdown of the enzyme enhances, the glucose response of GAL4-ChREBP, respectively. Moreover, the glucose analogue 2-deoxyglucose (2-DG), which is phosphorylated by hexokinase, but not further metabolized, effectively upregulates the transcription activity of ChREBP. In addition, over-expression of phosphofructokinase (PFK) 1 and 2, synergistically diminishes the glucose response of GAL4-ChREBP. These multiple lines of evidence support the conclusion that G-6-P mediates the activation of ChREBP.
KW - Carbohydrate response element binding protein (ChREBP)
KW - Glucose-6-phosphate (G-6-P)
KW - Transcriptional activation
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U2 - 10.1016/j.bbrc.2010.04.028
DO - 10.1016/j.bbrc.2010.04.028
M3 - Article
C2 - 20382127
AN - SCOPUS:77951848682
SN - 0006-291X
VL - 395
SP - 395
EP - 400
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -