1: J Biol Chem. 2003 Feb 28;278(9):6976-84. Epub 2002 Dec 18. 

Thrombin stimulation of vascular adhesion molecule-1 in endothelial cells is
mediated by protein kinase C (PKC)-delta-NF-kappa B and PKC-zeta-GATA signaling
pathways.

Minami T, Abid MR, Zhang J, King G, Kodama T, Aird WC.

Department of Molecular Medicine, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts 02215, USA.

We recently demonstrated that thrombin induces the expression of vascular
adhesion molecule-1 (VCAM-1) in endothelial cells by an NF-kappaB- and
GATA-dependent mechanism. In the present study, we describe the signaling
pathways that mediate this response. Thrombin stimulation of the VCAM-1 gene and
promoter in human umbilical vein endothelial cells was inhibited by
preincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002, the
protein kinase C (PKC)-delta inhibitor, rottlerin, a PKC-zeta peptide inhibitor,
or by overexpression of dominant negative (DN)-PKC-zeta. In electrophoretic
mobility shift assays, thrombin-mediated induction of NF-kappaB p65 binding to
two NF-kappaB motifs in the upstream promoter region of VCAM-1 was blocked by
LY294002 and rottlerin, whereas the inducible binding of GATA-2 to a tandem GATA
motif was inhibited by LY294002 and the PKC-zeta peptide inhibitor. In
co-transfection assays, thrombin stimulation of a minimal promoter containing
multimerized VCAM-1 NF-kappaB sites was inhibited by DN-PKC-delta but not
DN-PKC-zeta. In contrast, thrombin-mediated transactivation of a minimal
promoter containing tandem VCAM-1 GATA motifs was inhibited by DN-PKC-zeta but
not DN-PKC-delta. Finally, thrombin failed to induce VCAM-1 expression in
vascular smooth muscle cells. Taken together, these data suggest that the
endothelial cell-specific effect of thrombin on VCAM-1 expression involves the
coordinate activity of PKC-delta-NF-kappaB and PKC-zeta-GATA signaling pathways.

PMID: 12493764 [PubMed - indexed for MEDLINE]


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