The ERK1/2-hepatocyte nuclear factor 4alpha axis regulates human ABCC6 gene expression in hepatocytes.
ABCC6 mutations are responsible for the development of pseudoxanthoma elasticum, a rare recessive disease characterized by calcification of elastic fibers. Although ABCC6 is mainly expressed in the liver the disease has dermatologic, ocular, and cardiovascular symptoms. We investigated the transcriptional regulation of the gene and observed that hepatocyte growth factor (HGF) inhibits its expression in HepG2 cells via the activation of ERK1/2. Similarly, other factors activating the cascade also inhibited ABCC6 expression. We identified the ERK1/2 response element in the proximal promoter by luciferase reporter gene assays. This site overlapped with a region conferring the tissue-specific expression pattern to the gene and with a putative hepatocyte nuclear factor 4alpha (HNF4alpha) binding site. We demonstrated that HNF4alpha regulates the expression of ABCC6, acts through the putative binding site, and determines its cell type-specific expression. We also showed that HNF4alpha is inhibited by the activation of the ERK1/2 cascade. In conclusion we describe here the first regulatory pathway of ABCC6 expression showing that the ERK1/2-HNF4alpha axis has an important role in regulation of the gene.
de Boussac
Hugues
H
Institute of Enzymology, Hungarian Academy of Sciences, Karolina ut 29, 1113 Budapest, Hungary.
Ratajewski
Marcin
M
Sachrajda
Iwona
I
Köblös
Gabriella
G
Tordai
Attila
A
Pulaski
Lukasz
L
Buday
László
L
Váradi
András
A
Arányi
Tamás
T
D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009928:Organ Specificity; D018384:Oxidative Stress / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D024483:Vitamin K 3 / Q000494:pharmacology
D051557:Hepatocyte Nuclear Factor 4; D006873:Hydroquinones; D036341:Intercellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D024483:Vitamin K 3; C102029:ABCC6 protein, human; C018855:2-tert-butylhydroquinone
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