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B Activation in Endothelial Cells 1
Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York 14642
We addressed the regulatory function of mammalian target of rapamycin (mTOR) in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. Pretreatment of HUVECs with rapamycin, an inhibitor of mTOR, augmented thrombin-induced ICAM-1 expression. Inhibition of mTOR by this approach promoted whereas over-expression of mTOR inhibited thrombin-induced transcriptional activity of NF-
B, an essential regulator of ICAM-1 transcription. Analysis of the NF-B signaling pathway revealed that inhibition of mTOR potentiated IB kinase activation resulting in a rapid and persistent phosphorylation of IB
on Ser32 and Ser36, a requirement for IB degradation. Consistent with these data, we observed a more efficient and stable nuclear localization of RelA/p65 and, subsequently, the DNA binding activity of NF-B by thrombin following mTOR inhibition. These data define a novel role of mTOR in down-regulating thrombin-induced ICAM-1 expression in endothelial cells by controlling a delayed and transient activation of NF-B.
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