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J Surg Res. 2007 Sep;142(1):129-36. Epub 2007 Jul 5.

Down syndrome candidate region 1-like 1 (DSCR1-L1) mimics the inhibitory effects of DSCR1 on calcineurin signaling in endothelial cells and inhibits angiogenesis.

Author information

1
Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

Abstract

In endothelial cells, binding of vascular endothelial growth factor (VEGF) to VEGF receptor 2 leads to the activation of the serine/threonine phosphatase calcineurin, dephosphorylation of the nuclear factor of activated T-cells (NF-AT) transcription factors, translocation of NF-AT to the nucleus, and expression of angiogenesis-related genes such as Cox-2. Down syndrome candidate region 1 (DSCR1) is transactivated by NF-AT nuclear translocation, and subsequently inhibits calcineurin activity, forming a negative feedback loop. While DSCR1 has a clearly defined role as an endogenous inhibitor of VEGF-calcineurin-mediated angiogenesis in endothelial cells, the function of the DSCR1 family member, DSCR1-like 1 (DSCR1-L1), has not yet been investigated in endothelial cells. Here we show that a panel of pro-angiogenic factors, including VEGF, basic fibroblast growth factor (bFGF), angiopoietin 1, hepatocyte growth factor, as well as triiodo-l-thyronine (T(3)), does not induce DSCR1-L1 up-regulation in endothelial cells, while VEGF potently up-regulates DSCR1. To investigate the effects of DSCR1-L1 on endothelial cell function, we cloned the gene into a lentiviral vector and overexpressed DSCR1-L1 in human umbilical vein endothelial cells. Constitutive DSCR1-L1 overexpression prevented the nuclear translocation of NF-ATc1 in response to VEGF, underscoring its role as a calcineurin inhibitor. Additionally, DSCR1-L1-transduced cells inhibited VEGF-induced endothelial cell migration, proliferation, and tube formation by 36, 77, and 39%, respectively, compared to cells infected with control virus. Overexpression of DSCR1-L1 in the transformed endothelial cell line Sven 1 ras also resulted in decreased proliferation. Our findings demonstrate that DSCR1-L1 is constitutively expressed in endothelial cells and acts similar to DSCR1 in inhibiting calcineurin activity and restraining VEGF-mediated angiogenesis.

PMID:
17610901
PMCID:
PMC1995402
DOI:
10.1016/j.jss.2006.10.011
[Indexed for MEDLINE]
Free PMC Article

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