Involvement of nuclear factor-kappaB in endothelin-A-receptor-induced proliferation and inhibition of apoptosis.
Endothelins have been implicated in the regulation of cell proliferation, differentiation, and apoptosis, but the mechanisms of these complex events are not yet fully understood. Although the nuclear factor-kappaB (NF-kappaB) was shown to play a prominent role in the above processes, its participation in endothelin receptor A (ET(A)R) signaling has not been previously demonstrated. This study provides evidence that NF-kappaB is involved in ET(A)R-induced proliferation and inhibition of apoptosis. Endothelin (ET)-1, ET-3, and sarafotoxin b induce cell proliferation and prevent apoptosis induced by serum deprivation in a Chinese hamster lung (CCL39) cell line that stably expresses ET(A)R (CCL39ET(A)). Activation of ET(A)R resulted in enhanced DNA-binding activity of NF-kappaB and degradation of IkappaB-alpha. Expression of the dominant negative form of IkappaB-alpha (IkappaB deltaN) inhibited the proliferative activities mediated by ET(A)R as well as its anti-apoptotic activities. Treatment of the cells with prostaglandin A1, an inhibitor of IkappaB kinase-beta, reduced ET-1-induced proliferation and its anti-apoptotic effect. These findings indicate that the regulation of cell proliferation and apoptosis by ET(A)R is mediated by the ET(A)R-activated NF-kappaB.
Mangelus
M
M
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
Galron
R
R
Naor
Z
Z
Sokolovsky
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006224:Cricetinae; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D009154:Mutation / Q000235:genetics; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011454:Prostaglandins A / Q000494:pharmacology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism*; D014757:Viper Venoms / Q000378:metabolism* / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D016232:Endothelins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011454:Prostaglandins A; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; D016222:Fibroblast Growth Factor 2; D000072000:NF-KappaB Inhibitor alpha; C100573:prostaglandin A1