Hypoxia-Inducible Factor 1 Is an Inductor of Transcription Factor Activating Protein 2 Epsilon Expression during Chondrogenic Differentiation.
The transcription factor AP-2ε (activating enhancer-binding protein epsilon) is expressed in cartilage of humans and mice. However, knowledge about regulatory mechanisms influencing AP-2ε expression is limited. Using quantitative real time PCR, we detected a significant increase in AP-2ε mRNA expression comparing initial and late stages of chondrogenic differentiation processes in vitro and in vivo. Interestingly, in these samples the expression pattern of the prominent hypoxia marker gene angiopoietin-like 4 (Angptl4) strongly correlated with that of AP-2ε suggesting that hypoxia might represent an external regulator of AP-2ε expression in mammals. In order to show this, experiments directly targeting the activity of hypoxia-inducible factor-1 (HIF1), the complex mediating responses to oxygen deprivation, were performed. While the HIF1-activating compounds 2,2'-dipyridyl and desferrioxamine resulted in significantly enhanced mRNA concentration of AP-2ε, siRNA against HIF1α led to a significantly reduced expression rate of AP-2ε. Additionally, we detected a significant upregulation of the AP-2ε mRNA level after oxygen deprivation. In sum, these different experimental approaches revealed a novel role for the HIF1 complex in the regulation of the AP-2ε gene in cartilaginous cells and underlined the important role of hypoxia as an important external regulatory stimulus during chondrogenic differentiation modulating the expression of downstream transcription factors.
Institute of Biochemistry, University of Erlangen-Nuremberg, Fahrstrasse 17, 91054 Erlangen, Germany ; Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
Stephan
S
Niebler
Department of Trauma Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
Peter
P
Angele
Department of Trauma Surgery, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.
Richard
R
Kujat
Institute of Biochemistry, University of Erlangen-Nuremberg, Fahrstrasse 17, 91054 Erlangen, Germany.
Anja K
AK
Bosserhoff
D042682:Angiopoietins / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002356:Cartilage / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019902:Chondrocytes / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
D042682:Angiopoietins; D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D050656:Transcription Factor AP-2; D010100:Oxygen