CCAAT enhancer binding protein beta and hepatocyte nuclear factor 3beta are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression.
Alpha2HS-glycoprotein/fetuin-A (Ahsg) is a serum protein preventing soft tissue calcification. In trauma and inflammation, Ahsg is down-regulated and therefore considered a negative acute phase protein. Enhancement of Ahsg expression as a protective serum protein is desirable in several diseases including tissue remodelling after trauma and infection, kidney and heart failure, and cancer. Using reporter gene assays in hepatoma cells combined with electrophoretic mobility shift assays we determined that dexamethasone up-regulates hepatic Ahsg. A steroid response unit at position -146/-119 within the mouse Ahsg promoter mediates the glucocorticoid-induced increase of Ahsg mRNA. It binds the hepatocyte nuclear factor 3beta and CCAAT enhancer binding protein beta (C/EBP-beta). The up-regulation is mediated indirectly via glucocorticoid hormone-induced transcriptional up-regulation in C/EBP-beta protein. A high degree of sequence identity in mouse, rat and human Ahsg promoters suggests that the promoter is similarly up-regulated by dexamethasone in all three species. Therefore, our findings suggest that glucocorticoids may be used to enhance the level of Ahsg protein circulating in serum.
Wöltje
Michael
M
Interdisciplinary Center for Clinical Research (IZKF) BIOMAT, RWTH Aachen University Hospital, Pauwelsstr. 30, D-52074 Aachen, Germany. woeltje@rwth-aachen.de
Tschöke
Beate
B
von Bülow
Verena
V
Westenfeld
Ralf
R
Denecke
Bernd
B
Gräber
Steffen
S
Jahnen-Dechent
Willi
W
D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D016415:Sequence Alignment; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D060749:alpha-2-HS-Glycoprotein; D000509:alpha-Fetoproteins / Q000235:genetics*
C556354:AHSG protein, human; C556357:Ahsg protein, mouse; D001798:Blood Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D060749:alpha-2-HS-Glycoprotein; D000509:alpha-Fetoproteins; D051542:Hepatocyte Nuclear Factor 3-beta; D003907:Dexamethasone; D003513:Cycloheximide