COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction.
During embryonic lymphatic development, Prox1 homeobox transcription factor is expressed in a subset of venous blood vascular endothelial cells (BECs) in which COUP-TFII orphan nuclear receptor is highly expressed. Prox1 induces differentiation of BECs into lymphatic endothelial cells (LECs) by inducing the expression of various LEC markers including vascular endothelial growth factor receptor 3 (VEGFR3). However, the molecular mechanisms of how transcriptional activities of Prox1 are regulated are largely unknown. In the present study, we show that COUP-TFII plays important roles in the regulation of the function of Prox1. In BECs and LECs, Prox1 promotes the proliferation and migration toward VEGF-C by inducing the expression of cyclin E1 and VEGFR3, respectively. Gain-of-function studies showed that COUP-TFII negatively regulates the effects of Prox1 in BECs and LECs whereas loss-of-function studies showed that COUP-TFII negatively and positively regulates Prox1 in BECs and LECs, respectively. We also show that endogenous Prox1 and COUP-TFII physically interact in LECs and that both Prox1 and COUP-TFII bind to the endogenous cyclin E1 promoter. These results suggest that COUP-TFII physically and functionally interact during differentiation and maintenance of lymphatic vessels.
Yamazaki
Tomoko
T
Department of Molecular Pathology, Graduate School of Medicine,Global Center of Excellence Program for Integrative Life Science Based on the Study of Biosignaling Mechanisms, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Yoshimatsu
Yasuhiro
Y
Morishita
Yasuyuki
Y
Miyazono
Kohei
K
Watabe
Tetsuro
T
D051837:COUP Transcription Factor II; D019927:Cyclin E / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
D051837:COUP Transcription Factor II; D019927:Cyclin E; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3; D000098551:Prospero-Related Homeobox 1 Protein; C095569:NR2F2 protein, human