Inhibition of mammalian target of rapamycin potentiates thrombin-induced intercellular adhesion molecule-1 expression by accelerating and stabilizing NF-kappa B activation in endothelial cells.
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-kappaB, an essential regulator of ICAM-1 transcription. Analysis of the NF-kappaB signaling pathway revealed that inhibition of mTOR potentiated IkappaB kinase activation resulting in a rapid and persistent phosphorylation of IkappaBalpha on Ser32 and Ser36, a requirement for IkappaBalpha 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-kappaB 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-kappaB.
Minhajuddin
Mohd
M
Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York 14642, USA.
Fazal
Fabeha
F
Bijli
Kaiser M
KM
Amin
Md Ruhul
MR
Rahman
Arshad
A
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D047428:Protein Kinase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D013917:Thrombin; D020123:Sirolimus