Abrogation of the cell death response to oxidative stress by the c-Abl tyrosine kinase inhibitor STI571
Abrogation of the cell death response to oxidative stress by the c-Abl tyrosine kinase inhibitor STI571
复制标题
DOI：
10.1124/mol.63.2.276
复制
发表时间：
2003-02-01
影响因子：
3.6
通讯作者：
Kufe, D
中科院分区：
文献类型：
--
作者：
Kumar, S;Mishra, N;Kufe, D
正常的有氧代谢与活性氧(ROS)的产生有关，因此，诱导细胞凋亡和坏死。细胞对氧化应激的死亡反应被认为是导致衰老、神经退化和其他疾病的原因之一。ROS诱导的细胞凋亡和坏死涉及胞浆c-Abl酪氨酸激酶的激活，从而向线粒体发出信号。在此，我们证明了STI571，一种慢性髓系白血病bcr-Abl的抑制剂，在小鼠胚胎成纤维细胞和人U-937髓系白血病细胞对过氧化氢(H_2O_2)的反应中，阻断了c-Abl的激活。免疫荧光显微镜和亚细胞分级研究表明，STI571减少了H_2O_2诱导的c-Abl在两种细胞类型中对线粒体的靶向59%至85%。结果还表明，STI571可减轻过氧化氢引起的线粒体跨膜电位的丧失。与这些效应相一致，STI571根据细胞类型的不同，将对过氧化氢暴露的死亡反应抑制40%至80%。这些发现表明，STI571抑制c-Abl信号可以减轻细胞对氧化应激反应中的线粒体功能障碍和细胞死亡。
Normal aerobic metabolism is associated with the production of reactive oxygen species (ROS) and, consequently, the induction of apoptosis and necrosis. The cell death response to oxidative stress is thought to contribute to aging, neurological degeneration, and other disorders. ROS-induced apoptosis and necrosis involves activation of the cytoplasmic c-Abl tyrosine kinase and thereby signaling to mitochondria. Herein, we show that STI571, an inhibitor of Bcr-Abl in chronic myelogenous leukemia, blocks activation of c-Abl in the response of mouse embryo fibroblasts and human U-937 myeloid leukemia cells to hydrogen peroxide (H2O2). Immunofluorescence microscopy and subcellular fractionation studies demonstrate that STI571 decreases H2O2-induced targeting of c-Abl to mitochondria in the two cell types by 59 to 85%. The results also show that STI571 attenuates H2O2-induced loss of the mitochondrial transmembrane potential. In concert with these effects, STI571 inhibits the death response to H2O2 exposure by 40 to 80% depending on the cell type. These findings indicate that inhibition of c-Abl signaling by STI571 attenuates mitochondrial dysfunction and cell death in the cellular response to oxidative stress.