Role of c-Jun N-terminal kinase/p38 stress signaling in 1-β-d-arabinofuranosylcytosine-induced apoptosis

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• 作者：Stadheim ; Terrance A. ; Saluta ; Gilda R. ; Kucera ; Gregory L.
• 关键词：p38 ; JNK ; SAPK ; ERK ; 1-β ; -d-arabinofuranosylcytosine ; apoptosis ; PD098059 ; SB203580
• 刊名：Biochemical Pharmacology
• 出版年：2000
• 出版时间：February 15, 2000
• 年：2000
• 卷：59
• 期：4
• 页码：407-418
• 全文大小：751 K

文摘

1-β-d-Arabinofuranosylcytosine (ara-C) induced apoptosis in HL-60 cells, which was preceded by the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK). 2′-Amino-3′-methoxyflavone (PD098059) and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) were used to inhibit the activity of ERK and p38, respectively. SEK-AL, a dominant-negative mutant of SEK1, was transfected into HL-60 cells (HL-60/SEK-AL) to assess the role of JNK/SAPK activity in apoptosis. PD098059 (25 μM) inhibited ara-C-induced caspase-3-like activity but was ineffective in altering ara-C-mediated apoptotic DNA fragmentation and clonogenicity. On the other hand, SB203580 (20 μM) inhibited ara-C-induced caspase-3-like activity, apoptotic DNA fragmentation, and clonogenicity. The inhibition of JNK1 activation in HL-60/SEK-AL cells did not block ara-C-induced apoptotic DNA fragmentation. These results suggest that ara-C-induced apoptotic DNA fragmentation and loss of clonogenicity occur through a p38-dependent pathway.