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Int. J. Mol. Sci. 2013, 14(9), 18437-18456; doi:10.3390/ijms140918437
Article

CREG Promotes the Proliferation of Human Umbilical Vein Endothelial Cells through the ERK/Cyclin E Signaling Pathway

1,†
,
2,†
,
2,†
,
2
,
2
,
2
,
2
,
3
 and
2,*
1 Graduate School of Third Military Medical University, Chongqing 400038, China 2 Cardiovascular Research Institute and Key laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840, China 3 Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 25 June 2013 / Revised: 15 August 2013 / Accepted: 28 August 2013 / Published: 6 September 2013
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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Abstract

Cellular repressor of E1A-stimulated genes (CREG) is a recently discovered secreted glycoprotein involved in homeostatic modulation. We previously reported that CREG is abundantly expressed in the adult vascular endothelium and dramatically downregulated in atherosclerotic lesions. In addition, CREG participates in the regulation of apoptosis, inflammation and wound healing of vascular endothelial cells. In the present study, we attempted to investigate the effect of CREG on the proliferation of vascular endothelial cells and to decipher the underlying molecular mechanisms. Overexpression of CREG in human umbilical vein endothelial cells (HUVEC) was obtained by infection with adenovirus carrying CREG. HUVEC proliferation was investigated by flow cytometry and 5-bromo-2'-deoxy-uridine (BrdU) incorporation assays. The expressions of cyclins, cyclin-dependent kinases and signaling molecules were also examined. In CREG-overexpressing cells, we observed a marked increase in the proportion of the S and G2 population and a decrease in the G0/G1 phase population. The number of BrdU positively-stained cells also increased, obviously. Furthermore, silencing of CREG expression by specific short hairpin RNA effectively inhibited the proliferation of human umbilical vein endothelial cells (HUVEC). CREG overexpression induced the expression of cyclin E in both protein and mRNA levels to regulate cell cycle progression. Further investigation using inhibitor blocking analysis identified that ERK activation mediated the CREG modulation of the proliferation and cyclin E expression in HUVEC. In addition, blocking vascular endothelial growth factor (VEGF) in CREG-overexpressed HUVEC and supplementation of VEGF in CREG knocked-down HUVEC identified that the pro-proliferative effect of CREG was partially mediated by VEGF-induced ERK/cyclin E activation. These results suggest a novel role of CREG to promote HUVEC proliferation through the ERK/cyclin E signaling pathway.
Keywords: CREG; HUVEC; proliferation; cyclin E; ERK CREG; HUVEC; proliferation; cyclin E; ERK
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Tao, J.; Yan, C.; Tian, X.; Liu, S.; Li, Y.; Zhang, J.; Sun, M.; Ma, X.; Han, Y. CREG Promotes the Proliferation of Human Umbilical Vein Endothelial Cells through the ERK/Cyclin E Signaling Pathway. Int. J. Mol. Sci. 2013, 14, 18437-18456.

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