Effect of c-Abl tyrosine kinase on the cellular response to paclitaxel-induced microtubule damage

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 r esults in activation of c-Abl kinase. In 3T3 cells, the presence of c-Abl k inase increased paclitaxel-induced cell death. in Abl-proficient cells, pac litaxel produced a marked and prolonged G2/M arrest which peaked at 24 h an d a rapid and marked induction of p21(WAF1) which also peaked at 24 h. In A bl-deficient cells, the G2/M arrest induced by paclitaxel was less prominen t and shorter in duration and the effect of paclitaxel on p21(WAF1) express ion was reduced and delayed. Paclitaxel had no effect on p53 expression and MAPK phosphorylation. These findings indicate that, in 3T3 cells, c-Abl ki nase facilitates cell death and regulates G2/M arrest in response to paclit axel-induced microtubule damage in a pathway that is dependent on p21(WAF1) and independent of MAPK activity. (C) 2000 Cancer Research Campaign.