Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase.
Expression of the catalytic subunit of glucose-6-phosphatase (G6Pase) has recently been shown to be transactivated by the transcription factor FKHR. Insulin and conditions of energy depletion are known repressors of the G6Pase gene. Whereas insulin is known to inhibit G6Pase expression by phosphorylation and nuclear exclusion of FKHR, the mechanism of repression of G6Pase by energy depletion is unknown. Here, we have studied the effect of glucose starvation and AICAR, an activator of AMP-activated protein kinase (AMPK) on G6Pase expression and the expressional level of FKHR-protein in hepatic cells. Using a H4-hepatoma cell line stably overexpressing FKHR, we found that both glucose starvation and treatment of cells with AICAR strongly repressed G6Pase expression and led to an almost complete disappearance of the FKHR protein, whereas the levels of control proteins and FKHR mRNA were not affected. Our data suggest that AICAR and glucose starvation inhibit G6Pase expression by a reduction of the cellular level of FKHR, presumably mediated by specific degradation of the protein.
Barthel
Andreas
A
Institut für Pharmakologie und Toxikologie, RWTH Aachen, D-52057 Aachen, Germany. Andreas.Barthel@post.rwth-aachen.de
Schmoll
Dieter
D
Krüger
Klaus-Dieter
KD
Roth
Richard A
RA
Joost
Hans-Georg
HG
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D002149:Energy Intake; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000502:physiology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012265:Ribonucleotides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; C031143:AICA ribonucleotide; D005947:Glucose