Transcriptional control of the human aldehyde dehydrogenase 2 promoter by hepatocyte nuclear factor 4: inhibition by cyclic AMP and COUP transcription factors.
An important regulatory element (designated FP330-3') of the ALDH2 promoter mediates activation by hepatocyte nuclear factor 4 (HNF4). This activation of promoter constructs containing this element by HNF4 was reduced by nearly half by 8-Br-cAMP in H4IIEC3 cells, an effect that was blocked by inhibitors of protein kinase A (PKA). Cotransfection assays showed that COUP-TF I, ARP-1, or PPARdelta suppressed the ability of HNF4 to activate the reporter. The repression was potentiated by 8-Br-cAMP. Electrophoretic mobility shift assays revealed that treatment of hepatoma cells or cultured rat hepatocytes with 1 mM 8-Br-cAMP or glucagon reduced binding of FP330-3' by HNF4 by half. In vitro phosphorylation of HNF4 by PKA decreased binding to FP330-3'. Fasting reduced the ALDH2 protein level in liver and kidney, two tissues expressing HNF4, but not heart. These data suggest that ALDH2 expression can be suppressed by cAMP, most likely through phosphorylation of HNF4 by PKA, and this may account for the reduction in enzyme protein during fasting.
You
Min
M
Department of Medicine, Indiana University School of Medicine and Richard Roudebush Veteran's Affairs Medical Center, Indianapolis, Indiana 46202, USA. miyou@ioupui.edu
Fischer
Monika
M
Cho
Won Kyoo
WK
Crabb
David
D
D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D006528:Carcinoma, Hepatocellular; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D004789:Enzyme Activation; D005215:Fasting / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020868:Gene Silencing; D017930:Genes, Reporter; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000494:pharmacology* / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C403128:MLX protein, human; C497588:Nr2f2 protein, rat; C096127:ALDH2 protein, human; C095569:NR2F2 protein, human