Bcl-2-independent Bcr-Abl-mediated resistance to apoptosis:: protection is correlated with up regulation of Bcl-xL
Bcl-2-independent Bcr-Abl-mediated resistance to apoptosis:: protection is correlated with up regulation of Bcl-xL
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DOI：
10.1038/sj.onc.1201664
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发表时间：
1998-03-19
期刊：
影响因子：
8
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Amarante-Mendes, GP;McGahon, AJ;Green, DR
Bcr-Abl是在慢性髓性白血病（CML）细胞中发现的负责转化表型和对化疗药物耐药的分子，野生型HL-60是一种转化的前髓细胞系，对诱导凋亡的药物非常敏感。我们在这里表明，HL-60细胞中Bcr-Abl的表达使它们对多种药物诱导的凋亡具有极强的抵抗力。研究发现，bcr-abl的抗凋亡作用与细胞周期的阶段无关，针对bcr的反义寡核苷酸治疗降低了异位bcr-abl的表达，恢复了细胞凋亡的易感。先前已发现，影响自磷酸化位点和磷酸酪氨酸结合基序（FLVRES）的双重突变会损害成纤维细胞和造血细胞中bcr-abl的转化活性。然而，表达这种双突变分子的HL-60细胞表现出与表达野生型Bcr-Abl相同的抗凋亡水平。有趣的是，野生型和突变型Bcr-Abl诱导HL-60细胞中Bcl-2的显著下调和Bcl-x(L)的水平升高。Bar水平不随Bcr-Abl的存在而变化，靶向bcl-x的反义寡核苷酸下调bcl-x (L)的表达，增加HL-60的易感性。Bcr-Abl细胞对stausporine的反应。重要的是，与HL-60相比，过表达Bcl-x(L)的HL-60细胞Bcl-x(L)的表达更高，但对凋亡的抗性更低。bcr - abl细胞。本研究结果表明，Bcr-Abl是一种强大的哺乳动物抗凋亡分子，可以独立于Bcl-2、Bcl-x(L)起作用，然而，Bcr-Abl介导的HL-60细胞的凋亡抗性似乎部分参与。
Bcr-Abl is the molecule responsible for both the transformation phenotype and the resistance to chemotherapeutic drugs found in chronic myelogenous leukemia (CML) cells, Wild-type HL-60, a transformed pro-myelocytic cell line, is very susceptible to apoptosis-inducing agents, We show here that expression of Bcr-Abl in HL-60 cells rendered them extremely resistant to apoptosis induced by a wide variety of agents, The anti-apoptotic effect of Bcr-Abl was found to be independent of the phase of the cell cycle, Treatment with antisense oligonucleotides directed to bcr decreased the expression of the ectopic bcr-abl and restored susceptibility to apoptosis, Double mutations affecting the autophosphorylation site and the phosphotyrosine-binding motif (FLVRES) have been previously shown to impair the transforming activity of Bcr-Abl in fibroblasts and hematopoietic cells, however HL-60 cells expressing this double mutant molecule exhibited the same level of resistance to apoptosis as those expressing the wild-type Bcr-Abl. Interestingly, wild type and mutant Bcr-Abl induced in HL-60 cells a dramatic down regulation of Bcl-2 and increased the levels of Bcl-x(L). The level of Bar did not change in response to the presence of Bcr-Abl, Antisense oligonucleotides targeted to bcl-x downregulated the expression of Bcl-x(L) and increased the susceptibility of HL-60.Bcr-Abl cells to staurosporine. Importantly, HL-60 cells overexpressing Bcl-x(L) showed higher expression of Bcl-x(L) but lower resistance to apoptosis when compared to HL-60.Bcr-Abl cells. The results described here show that Bcr-Abl is a powerful mammalian anti-apoptotic molecule and can act independently of Bcl-2, Bcl-x(L), however, seems to participate in part in Bcr-Abl-mediated resistance to apoptosis in HL-60 cells.