Multani A S, Ozen M, Narayan S, Kumar V, Chandra J, McConkey D J, Newman R A, Pathak S
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Neoplasia. 2000 Jul-Aug;2(4):339-45. doi: 10.1038/sj.neo.7900105.
Chromosomal abnormalities involving telomeric associations (TAs) often precede replicative senescence and abnormal chromosome configurations. We report here that telomere cleavage following exposure to proapoptotic agents is an early event in apoptosis. Exposure of human and murine cancer cells to a variety of pro-apoptotic stimuli (staurosporine, thapsigargin, anti-Fas antibody, and cancer chemotherapeutic agents) resulted in telomere cleavage and aggregation, and finally their extrusion from the nuclei. Telomere loss was associated with arrest of cells in G2/M phase and preceded DNA fragmentation. Telomere erosion and subsequent large-scale chromatin cleavage were inhibited by overexpression of the anti-apoptotic protein, bcl-2, and two peptide caspase inhibitors (BACMK and zVADfmk), indicating that both events are regulated by caspase activation. The results demonstrate that telomere cleavage is an early chromatin alteration detected in various cancer cell lines leading to drug-induced apoptosis, and suggest that this event contributes to mitotic catastrophe and induction of cell death. Results also suggest that the decrease of telomeric-repeat binding factor 2 (TRF2) may be the earliest event in the ara-C-induced telomere shortening, induction of endoreduplication and chromosomal fragmentation leading to cell death.
涉及端粒联合（TAs）的染色体异常通常先于复制性衰老和异常染色体构型出现。我们在此报告，暴露于促凋亡剂后发生的端粒切割是细胞凋亡的早期事件。将人和小鼠癌细胞暴露于多种促凋亡刺激因素（星形孢菌素、毒胡萝卜素、抗Fas抗体和癌症化疗药物）会导致端粒切割和聚集，最终使其从细胞核中挤出。端粒缺失与细胞停滞在G2/M期相关，并先于DNA片段化出现。抗凋亡蛋白bcl-2以及两种肽类半胱天冬酶抑制剂（BACMK和zVADfmk）的过表达可抑制端粒侵蚀及随后的大规模染色质切割，这表明这两个事件均受半胱天冬酶激活的调控。结果表明，端粒切割是在各种癌细胞系中检测到的导致药物诱导凋亡的早期染色质改变，提示该事件促成有丝分裂灾难和细胞死亡的诱导。结果还表明，端粒重复结合因子2（TRF2）的减少可能是阿糖胞苷诱导端粒缩短、内复制诱导和染色体片段化导致细胞死亡的最早事件。
