Dan S, Naito M, Tsuruo T
Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo.
Cell Death Differ. 1998 Aug;5(8):710-5. doi: 10.1038/sj.cdd.4400400.
The BCR - ABL tyrosine kinase has been implicated as the cause of Philadelphia chromosome (Ph1)-positive leukemias. We report herein that CGP 57148, a selective inhibitor of the ABL tyrosine kinase, caused apoptosis specifically in bcr - abl-positive chronic myelogenous leukemia (CML) cells, K562 and KYO-1. Upon treatment with CGP 57148, CRKL, a specific substrate for BCR - ABL that propagates signals via phosphatidylinositol-3' kinase (PI3K), was dephosphorylated, indicating inhibition of BCR - ABL tyrosine kinase at the cellular level. Likewise, MAPK/ERK, a downstream mediator of Ras, was also dephosphorylated. Caspase activation and cleavage of retinoblastoma protein (pRB) accompanied the development of CGP 57148-induced apoptosis. Inhibition of caspase suppressed apoptosis and the cleavage of pRB, and in turn arrested cells in the G1 phase. These results indicate that CGP 57148 shows apoptogenic and anti-proliferative effects on bcr - abl-positive cells by blocking BCR - ABL-initiated signaling pathways.
BCR-ABL酪氨酸激酶被认为是费城染色体（Ph1）阳性白血病的病因。我们在此报告，ABL酪氨酸激酶的选择性抑制剂CGP 57148可特异性地诱导bcr-abl阳性慢性粒细胞白血病（CML）细胞K562和KYO-1发生凋亡。用CGP 57148处理后，作为BCR-ABL特异性底物并通过磷脂酰肌醇-3'激酶（PI3K）传递信号的CRKL发生去磷酸化，表明在细胞水平上BCR-ABL酪氨酸激酶受到抑制。同样，Ras的下游介质MAPK/ERK也发生了去磷酸化。半胱天冬酶激活和视网膜母细胞瘤蛋白（pRB）的裂解伴随着CGP 57148诱导的凋亡的发生。抑制半胱天冬酶可抑制凋亡和pRB的裂解，进而使细胞停滞在G1期。这些结果表明，CGP 57148通过阻断BCR-ABL启动的信号通路，对bcr-abl阳性细胞显示出凋亡诱导和抗增殖作用。
