Activation of the VEGFR1 chromatin domain: an angiogenic signal-ETS1/HIF-2alpha regulatory axis
Authors: Soma Ray
Jay L Vivian
Soumen Paul
Debasree Dutta
Journal: Journal of Biological Chemistry (2008)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Angiogenesis; VEGF; FGF2; VEGFR1; EGF
Affiliations: Institute of Maternal-Fetal Biology and the Division of Cancer and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160., Institute of Maternal-Fetal Biology and the Division of Cancer and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160. Electronic address: .

Abstract:  Angiogenesis is induced by multiple growth factors including vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2). In vascular endothelium VEGF signals through two receptor-tyrosine kinases, VEGFR1 and VEGFR2. The VEGFR1 gene encodes both a receptor-tyrosine kinase and a secreted splice variant, soluble VEGFR1. Whereas VEGFR1 is essential for vascular development, mechanisms that regulate VEGFR1 expression in endothelial cells are poorly understood. We demonstrate here that in endothelial cells, FGF2 and epidermal growth factor (EGF) signaling induce VEGFR1 mRNA expression in a combinatorial fashion. EGF/FGF2-mediated VEGFR1 induction is mediated via functional interaction of transcription factors ETS1 and HIF-2alpha. Mechanistic analyses revealed that in endothelial cells EGF/FGF2 signaling induces ETS1 expression, increases HIF-2alpha protein level in absence of hypoxia, and recruits both ETS1 and HIF-2alpha to the VEGFR1 chromatin domain. Knockdown of ETS1 and HIF-2alpha by RNA interference inhibits EGF/FGF2-induced VEGFR1 expression, and loss of expression is associated with impaired RNA-polymerase II recruitment and histone modifications at the VEGFR1 promoter region. In addition, using a mouse embryonic stem cell in vitro differentiation system, we found that induction of VEGFR1 in embryoid bodies is also associated with ETS1 and HIF-2alpha recruitment to the VEGFR1 locus. These results establish an angiogenic signal-ETS1/HIF-2alpha axis that regulates the VEGFR1 chromatin domain to induce VEGFR1 transcription in endothelial cells and in differentiating embryonic stem cells. 

Retracted: No

PubPeer comments:
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 Hi, This is Soumen Paul, the s corresponding author of those two papers. First of all, I am extremely surprised and embarrassed that this mistake has happened. However, this is an unintentional mistake. These two papers were the first two papers from my laboratory and experiments for these papers were conducted simultaneously at my new lab in 2008-2009. I was a new Assistant Professor at that time and was working on the bench, writing grants and writing these papers simultaneously. We were using both alpha tubulin and beta actin as loading controls for generating definitive data and we were performing multiple repeat experiments. Thus, while working on multiple figures using cropped images of western blots of loading controls at the same time, we might have mislabeled it and this mistake happened. (Sometimes the gel doc images were also inverted). However, I want to reiterate the fact that the actual scientific findings of these two papers were repeated multiple times and are also validated by other laboratories. The findings from these two manuscripts have also provided new paradigm for scientific research. For example, the importance of GATA factors in trophoblast cells are now well established and accepted by scientists all over the world. The importance of ETS2 in endothelial cell biology is also well established. Also, If any one still has any suspicion about our actual findings in these manuscripts, he or she is welcome in my laboratory to do those experiments. Nevertheless, this mistake with loading controls is extremely embarrassing and I am really sorry that as the corresponding author I missed it. ,