Journal
ONCOGENE
Volume 27, Issue 32, Pages 4402-4410Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.82
Keywords
cell cycle; cancer; G1 arrest; paclitaxel; mitosis
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Paclitaxel (PTX) and other microtubule inhibitors cause mitotic arrest. However, low concentrations of PTX (low PTX) paradoxically cause G1 arrest ( without mitotic arrest). Here, we demonstrated that unexpectedly, low PTX did not cause G1 arrest in the first cell cycle and did not prevent cells from passing through S phase and entering mitosis. Mitosis was prolonged but cells still divided, producing either two or three cells (tripolar mitosis), thus explaining a sub G1 peak caused by low PTX. Importantly, sub G1 cells were viable and non-apoptotic. Some cells fused back and then progressed to mitosis, frequently producing three cells again before becoming arrested in the next cell-cycle interphase. Thus, low PTX caused postmitotic arrest in second and even the third cell cycles. By increasing concentration of PTX, tripolar mitosis was transformed to mitotic slippage, thus eliminating a sub G1 peak. Time-lapse microscopy revealed that prolonged mitosis ensured a p53-dependent postmitotic arrest. We conclude that PTX directly affects cells only in mitosis and the duration of mitosis determines cell fate, including p53-dependent G1-like arrest.
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