Nehmé A, Lee B L, Baskaran R, Zhang Q, Lin X, Christen R D
Department of Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA, 92093-0058, USA.
Br J Cancer. 2000 Nov;83(10):1360-6. doi: 10.1054/bjoc.2000.1440.
DNA damage has been shown to activate c-Abl tyrosine kinase. We now report that, in addition to DNA damage, microtubule damage induced by paclitaxel results in activation of c-Abl kinase. In 3T3 cells, the presence of c-Abl kinase increased paclitaxel-induced cell death. In Abl-proficient cells, paclitaxel produced a marked and prolonged G2/M arrest which peaked at 24 h and a rapid and marked induction of p21(WAF1)which also peaked at 24 h. In Abl-deficient cells, the G2/M arrest induced by paclitaxel was less prominent and shorter in duration and the effect of paclitaxel on p21(WAF1)expression was reduced and delayed. Paclitaxel had no effect on p53 expression and MAPK phosphorylation. These findings indicate that, in 3T3 cells, c-Abl kinase facilitates cell death and regulates G2/M arrest in response to paclitaxel-induced microtubule damage in a pathway that is dependent on p21(WAF1)and independent of MAPK activity.
DNA损伤已被证明可激活c-Abl酪氨酸激酶。我们现在报告，除了DNA损伤外，紫杉醇诱导的微管损伤也会导致c-Abl激酶激活。在3T3细胞中，c-Abl激酶的存在增加了紫杉醇诱导的细胞死亡。在Abl基因功能正常的细胞中，紫杉醇产生显著且持久的G2/M期阻滞，在24小时达到峰值，同时p21（WAF1）迅速且显著诱导，也在24小时达到峰值。在Abl基因缺陷的细胞中，紫杉醇诱导的G2/M期阻滞不那么明显且持续时间较短，紫杉醇对p21（WAF1）表达的影响降低且延迟。紫杉醇对p53表达和MAPK磷酸化没有影响。这些发现表明，在3T3细胞中，c-Abl激酶促进细胞死亡，并在依赖p21（WAF1）且独立于MAPK活性的途径中，响应紫杉醇诱导的微管损伤调节G2/M期阻滞。
