DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression.
Expression of glucose-6-phosphatase (G6Pase), one of the rate-limiting enzymes of hepatic gluconeogenesis, has recently been shown to be transactivated by the transcription factor FKHR. One of the proteins known to directly interact with FKHR is the nuclear protein kinase DYRK1A. In order to study the effects of DYRK1A on G6Pase gene expression, we generated a H4IIEC3 rat hepatoma cell line stably expressing DYRK1A by retroviral infection. Overexpression of DYRK1A increased the expression of G6Pase about threefold, as determined by Northern blotting. In transiently transfected HepG2 cells, co-expression of DYRK1A and a G6Pase promoter construct increased G6Pase promoter activity about twofold. This effect of DYRK1A was independent of its kinase activity, since a kinase-dead DYRK1A mutant as well as a point mutant of the phosphorylation site of DYRK1A in FKHR (Ser329Ala) failed to affect the effect of DYRK1A on the G6Pase expression. The effect of DYRK on the G6Pase promoter activity was produced by the isoforms DYRK1A and DYRK1B, which are localized in the nucleus, but not by DYRK2. Mutations of the FKHR-binding sites in the G6Pase promoter markedly reduced the effect of DYRK1 on the G6Pase promoter activity. In summary, the data suggest that DYRK1 is a specific co-activator of FKHR, independent of its kinase activity.
von Groote-Bidlingmaier
Florian
F
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät der RWTH, D-52057 Aachen, Germany.
Schmoll
Dieter
D
Orth
Hans Martin
HM
Joost
Hans Georg
HG
Becker
Walter
W
Barthel
Andreas
A
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097603:Dyrk Kinases; D000071161:Forkhead Box Protein O1
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D005952:Glucose-6-Phosphatase; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D014157:Transcription Factors; D000097603:Dyrk Kinases; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1