Tumor necrosis factor-alpha- or lipopolysaccharide-induced expression of the murine P-selectin gene in endothelial cells involves novel kappaB sites and a variant activating transcription factor/cAMP response element.

Abstract

Tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) increases expression of the P-selectin gene in murine, but not in human, endothelial cells. These mediators augment expression of a reporter gene driven by the murine, but not the human, P-selectin promoter in transfected endothelial cells. The regions from -593 to -474 and from -229 to -13 in the murine P-selectin promoter are required for TNF-alpha or LPS to stimulate reporter gene expression. Within these regions, we identified two tandem kappaB elements, a reverse-oriented kappaB site and a variant activating transcription factor/cAMP response element (ATF/CRE), that participate in TNF-alpha- or LPS-induced expression. The tandem kappaB elements bound to NF-kappaB heterodimers and p65 homodimers, the reverse-oriented kappaB site bound to p65 homodimers, and the variant ATF/CRE bound to nuclear proteins that included activating transcription factor-2. Mutations in each individual element eliminated binding to nuclear proteins and decreased by 20-60% the TNF-alpha- or LPS-induced expression of a reporter gene driven by the murine P-selectin promoter in transfected endothelial cells. Simultaneous mutations of all elements further decreased, but did not abolish, induced expression. Co-overexpression of p50 and p65 enhanced murine P-selectin promoter activity in a kappaB site-dependent manner. These data indicate that the kappaB sites and the variant ATF/CRE are required for TNF-alpha or LPS to optimally induce expression of the murine P-selectin gene. The presence of these elements in the murine, but not the human, P-selectin gene may explain in part why TNF-alpha or LPS stimulates transcription of P-selectin in a species-specific manner.

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@article{Pan1998TumorNF, title={Tumor necrosis factor-alpha- or lipopolysaccharide-induced expression of the murine P-selectin gene in endothelial cells involves novel kappaB sites and a variant activating transcription factor/cAMP response element.}, author={Jing Pan and Lijuan Xia and Longbiao Yao and Rodger P McEver}, journal={The Journal of biological chemistry}, year={1998}, volume={273 16}, pages={10068-77} }