Abstract
Developmental endothelial locus-1 (Del-1) is an endothelium-derived anti-inflammatory molecule that is downregulated by inflammatory stimuli. Little is known about the molecular mechanisms by which Del-1 transcription is regulated. In the present study, a DNA sequence upstream of the Del-1 gene was analyzed and putative p53 response elements (p53REs) were identified. An approximately 2 kb fragment upstream of the translation start site displayed the highest Del-1 transcriptional activity, and the transcriptional activity of this fragment was enhanced by overexpression of p53. Chemical activation of endogenous p53 elevated the levels of Del-1 mRNA. Site-directed mutagenesis of CATG in the consensus sequences of the 2 kb fragment to TATA significantly reduced the transcription of Del-1. Chromatin immunoprecipitation revealed recruitment of p53 to the p53REs of the Del-1 promoter, resulting in increased Del-1 transcription. Finally, primary endothelial cells isolated from mice with reduced levels of p53 showed a decrease in Del-1 mRNA compared to wild-type endothelial cells. Moreover, Del-1 reciprocally enhanced p53 expression in primary endothelial cells. Thus, these findings suggest that Del-1 is a novel transcriptional target gene of p53.
Highlights
Developmental endothelial locus-1 (Del-1, called Edil3) is a 52 kD glycoprotein that harbors three epidermal growth factor-like domains and two discoidin domains
We previously demonstrated that Del-1 is expressed in endothelial cells, in which Del-1 expression is downregulated by inflammatory stimuli such as tumor necrosis factor (TNF)-α, lipopolysaccharide (LPS), and interleukin (IL)-17 [6, 7]
A luciferase assay revealed that mutation of either p53 response elements (p53REs) significantly reduced the transcriptional activity (Fig. 3), demonstrating an important role for these p53REs in the transcriptional regulation of Del-1
Summary
Developmental endothelial locus-1 (Del-1, called Edil3) is a 52 kD glycoprotein that harbors three epidermal growth factor-like domains and two discoidin domains. Del-1is secreted by endothelial cells, it can be associated with proteoglycans on the cell surface or can bind to endothelial integrins such as αvβ and αvβ. Del-1 has been proposed to be implicated in the vascularization, angiogenesis, apoptosis, adhesion, migration, and proliferation, the involvement of Del-1 in these cellular activities remains controversial [15]. We previously reported that Del-1 competes with the endothelial cell adhesion molecule ICAM-1 for binding to leukocyte function-associated antigen 1 (LFA-1), thereby inhibiting leukocyte adhesion and subsequent migration through the vessel barrier. Del-1 inhibits the duration and magnitude of the inflammatory response [6].
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