부산대학교 도서관

The signaling mechanism underlying aburatubolactamC-induced FasL upregulation was investigated in humanJurkat T cells. After treatment with aburatubolactam C, thesrc-family PTKs p56lck and p59fyn, and MAP kinases ERK2and JNK1, were activated prior to FasL upregulation. Bothp56lck and p59fyn were directly activated 2.4- and 2.2-fold,respectively, in vitro by aburatubolactam C. The aburatubolactamC-induced cellular changes, including the activation of ERK2and JNK1, and FasL upregulation, were completely preventedby the PTK inhibitor genistein. The activation of proteinkinase C (PKCδ, ε, and μ) was also induced followingaburatubolactam C treatment. Although the activation of p56lckand tyrosine phosphorylation of the cellular proteins were notblocked by the PKC inhibitor GF109203X, the activation ofERK2 was completely abrogated, along with a detectablyenhanced JNK1 activation, FasL upregulation, and apoptosis.However, the FasL upregulation and apoptosis were significantlyinhibited by the PKC activator PMA, with a remarkableincrease in the ERK2 activation. The cytotoxic effect ofaburatubolactam C was reduced in the presence of the anti-Fas neutralizing antibody ZB-4. Although ectopic expressionof Bcl-2 failed to completely block the cytotoxicity ofaburatubolactam C, it was clearly suppressed. The c-Fos mRNAexpression was upregulated in a biphasic manner, where thesecond phasic expression overlapped with the FasL upregulation.Accordingly, these results demonstrate that aburatubolactamC-induced apoptosis is exerted, at least in part, by FasLupregulation dictated by activation of the PTK (p56lck andp59fyn)/JNK1 pathway, which is negatively affected by theconcurrent activation of the PKC/ERK2 pathway proximal toPTK activation.