Park D S, Morris E J, Padmanabhan J, Shelanski M L, Geller H M, Greene L A
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
J Cell Biol. 1998 Oct 19;143(2):457-67. doi: 10.1083/jcb.143.2.457.
Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cells both in vitro and in vivo. Accordingly, it has become important to understand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important role in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic and cortical neurons against DNA-damaging conditions. We show that Sindbis virus-induced expression of CKIs p16(ink4), p21(waf/cip1), and p27(kip1), as well as DN-Cdk4 and 6, but not DN-Cdk2 or 3, protect sympathetic neurons against UV irradiation- and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent camptothecin. Finally, in consonance with our hypothesis and these results, cyclin D1-associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results suggest that postmitotic neurons may utilize Cdk4 and 6, signals that normally control proliferation, to mediate death signaling resulting from DNA-damaging conditions.
先前的报告表明，包括某些抗癌治疗药物在内的DNA损伤处理在体外和体内均会导致有丝分裂后神经细胞死亡。因此，了解控制这一过程的信号事件变得很重要。我们最近推测，某些细胞周期分子可能在DNA损伤引发的神经元死亡信号传导中起重要作用。因此，我们研究了细胞周期蛋白依赖性激酶抑制剂（CKIs）和显性负性（DN）细胞周期蛋白依赖性激酶（CDK）是否能保护交感神经元和皮质神经元免受DNA损伤条件的影响。我们发现，辛德毕斯病毒诱导的CKIs p16(ink4)、p21(waf/cip1)和p27(kip1)以及DN-Cdk4和6的表达，但不是DN-Cdk2或3的表达，可保护交感神经元免受紫外线照射和阿糖胞苷诱导的死亡。我们还证明，CKIs p16和p27以及DN-Cdk4和6，但不是DN-Cdk2或3，可保护皮质神经元免受DNA损伤剂喜树碱的影响。最后，与我们的假设和这些结果一致，喜树碱处理后，皮质神经元中细胞周期蛋白D1相关激酶活性迅速且高度升高。这些结果表明，有丝分裂后神经元可能利用通常控制增殖的Cdk4和6信号来介导DNA损伤条件下的死亡信号传导。
