Maruo A, Oishi I, Sada K, Nomi M, Kurosaki T, Minami Y, Yamamura H
Department of Biochemistry, Kobe University, School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Int Immunol. 1999 Sep;11(9):1371-80. doi: 10.1093/intimm/11.9.1371.
Several sets of non-receptor protein tyrosine kinases (PTK) play important roles in apoptosis induced by various extracellular stresses. Anti-cancer drugs induce cellular DNA damage and cytotoxic events, leading to apoptotic cell death. We utilized the established chicken B cell line, DT40 cells and their derived mutants, lacking the respective PTK [DT40/Syk(-), DT40/Lyn(-) and DT40/Btk(-)], to examine a role of these PTK in apoptotic processes induced by anti-cancer drugs. All anti-cancer drugs examined induced apoptosis of wild-type DT40 cells. Interestingly,DT40/Lyn(-), but not DT40/Syk(-) and DT40/Btk(-) cells, become resistant to apoptosis induced by adriamycin and etoposide, topoisomerase II (Topo II) inhibitory agents, compared to wild-type DT40 cells, as assessed by DNA fragmentation and TUNEL analyses. Ectopic expression of Fyn, another Src family member, in DT40/Lyn(-) cells restores largely the susceptibility of the cells against Topo II inhibitor-induced apoptosis. Furthermore, it was found that Topo II inhibitors activate c-Jun N-terminal kinase (JNK) slightly in both wild-type and DT40/Lyn(-) cells to similar extents. Collectively, these results suggest that Lyn is involved in Topo II inhibitor-induced apoptotic signaling in DT40 cells independent of JNK.
几组非受体蛋白酪氨酸激酶（PTK）在各种细胞外应激诱导的细胞凋亡中发挥重要作用。抗癌药物会诱导细胞DNA损伤和细胞毒性事件，导致细胞凋亡死亡。我们利用已建立的鸡B细胞系DT40细胞及其缺失相应PTK的衍生突变体[DT40/Syk(-)、DT40/Lyn(-)和DT40/Btk(-)]，来研究这些PTK在抗癌药物诱导的凋亡过程中的作用。所检测的所有抗癌药物均诱导野生型DT40细胞凋亡。有趣的是，与野生型DT40细胞相比，通过DNA片段化和TUNEL分析评估，DT40/Lyn(-)细胞对阿霉素和依托泊苷（拓扑异构酶II（Topo II）抑制剂）诱导的凋亡具有抗性，而DT40/Syk(-)和DT40/Btk(-)细胞则没有。在DT40/Lyn(-)细胞中异位表达另一个Src家族成员Fyn，在很大程度上恢复了细胞对Topo II抑制剂诱导凋亡的敏感性。此外，还发现Topo II抑制剂在野生型和DT40/Lyn(-)细胞中均能轻微激活c-Jun氨基末端激酶（JNK），且程度相似。总体而言，这些结果表明Lyn在DT40细胞中参与Topo II抑制剂诱导的凋亡信号传导，且与JNK无关。
