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 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.
Nehmé
A
A
Department of Medicine, University of California, 9500 Gilman Drive, San Diego, La Jolla, CA, 92093-0058, USA.
Lee
B L
BL
Baskaran
R
R
Zhang
Q
Q
Lin
X
X
Christen
R D
RD
D016475:3T3 Cells; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016313:Genes, abl / Q000235:genetics*; D051379:Mice; D008870:Microtubules / Q000473:pathology / Q000648:ultrastructure*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel