Ahmed Wesam, Rahmani Mohamed, Dent Paul, Grant Steven
Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298, USA.
Cell Cycle. 2004 Oct;3(10):1305-11. doi: 10.4161/cc.3.10.1161. Epub 2004 Oct 6.
The functional significance of the cyclin-dependent kinase inhibitor (CDKI) p21(Cip1/WAF1) in paclitaxel-mediated lethality was examined in p53-null human leukemia cells (U937 and Jurkat). In these cells, paclitaxel exposure failed to induce p21(Cip1/Waf1) expression. Nevertheless, stable expression of U937 cells with a p21(Cip1/WAF1) antisense construct blocked paclitaxel-induced G(2)M arrest and increased mitochondrial injury, caspase activation, apoptosis, and loss of clonogenic potential. Consistent with these results, enforced expression of p21(Cip1/WAF1) in Jurkat cells increased the percentage of cells arrested in G2M and attenuated paclitaxel-mediated mitochondrial injury and apoptosis. Unexpectedly, enforced expression of p21(Cip1/WAF1) diminished paclitaxel-mediated inactivation of ERK, and reduced paclitaxel-induced activation of JNK as well as Bcl-2 phosphorylation. Together, these findings suggest that p21(Cip1/WAF1) partially protects p53-null human leukemia cells from paclitaxel-mediated lethality, and raise the possibility that p21(Cip1/WAF1)-associated perturbations in signal transduction pathways as well as Bcl-2 phosphorylation status may play a role in this phenomenon.
在p53基因缺失的人白血病细胞（U937和Jurkat）中，研究了细胞周期蛋白依赖性激酶抑制剂（CDKI）p21（Cip1/WAF1）在紫杉醇介导的细胞致死性中的功能意义。在这些细胞中，暴露于紫杉醇未能诱导p21（Cip1/Waf1）表达。然而，用p21（Cip1/WAF1）反义构建体稳定转染U937细胞，可阻断紫杉醇诱导的G（2）M期阻滞，并增加线粒体损伤、半胱天冬酶激活、细胞凋亡以及克隆形成潜力的丧失。与这些结果一致，在Jurkat细胞中强制表达p21（Cip1/WAF1）可增加停滞在G2M期的细胞百分比，并减轻紫杉醇介导的线粒体损伤和细胞凋亡。出乎意料的是，强制表达p21（Cip1/WAF1）可减少紫杉醇介导的ERK失活，并降低紫杉醇诱导的JNK激活以及Bcl-2磷酸化。总之，这些发现表明p21（Cip1/WAF1）可部分保护p53基因缺失的人白血病细胞免受紫杉醇介导的致死性，并增加了信号转导通路中与p21（Cip1/WAF1）相关的扰动以及Bcl-2磷酸化状态可能在此现象中起作用的可能性。
