title: Involvement of nuclear factor-kappaB in endothelin-A-receptor-induced proliferation and inhibition of apoptosis.
abstract: 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.
authors.affiliation: Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Mangelus
authors.forename: R
authors.initials: R
authors.lastname: Galron
authors.forename: Z
authors.initials: Z
authors.lastname: Naor
authors.forename: M
authors.initials: M
authors.lastname: Sokolovsky
mesh_terms: 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
chemical_list: 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