细胞生物学
支票1
DNA损伤
生物
拓扑异构酶
激酶
细胞凋亡
程序性细胞死亡
DNA断裂
DNA修复
细胞周期检查点
细胞周期
癌症研究
生物化学
DNA
作者
Olivier Sordet,Qasim Khan,Kurt W. Kohn,Yves Pommier
出处
期刊:Current medicinal chemistry
[Bentham Science]
日期:2003-07-01
卷期号:3 (4): 271-290
被引量:210
标识
DOI:10.2174/1568011033482378
摘要
Topoisomerase inhibitors are among the most efficient inducers of apoptosis. The main pathways leading from topoisomerase-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by proapoptotic molecules released from mitochondria. In some cells, apoptotic response also involves the death receptor Fas (APO-1 / CD95). The engagement of these apoptotic effector pathways is tightly controlled by upstream regulatory pathways that respond to DNA lesions-induced by topoisomerase inhibitors in cells undergoing apoptosis. These include the proapoptotic Chk2, c-Abl and SAPK / JNK pathways, the survival PI(3)kinase-Akt-dependent pathway and the transcription factors p53 and NF-κB. Initiation of cellular responses to DNA lesions-induced by topoisomerase inhibitors is ensured by the protein kinases DNA-PK, ATM and ATR, which bind to DNA breaks. These kinases commonly called "DNA sensors" mediate their effects (DNA repair, cell cycle arrest and / or apoptosis) by phosphorylating a large number of substrates, including several downstream kinases such as c-Abl and the checkpoint protein Chk2. c-Abl induces apoptosis by activating cell death pathways (e.g., SAPK, p53 and p73) and inhibiting cell survival pathways [e.g., PI(3)kinase]. The DNA-damage regulating kinase Chk2, in addition to its role in cell cycle arrest and / or DNA repair, can induce apoptosis by phosphorylation / activation of the promyelocytic leukemia (PML) protein and p53. Finally, we will review the recent observations that support a role for topoisomerases in chromatin fragmentation during the execution phase of apoptosis.
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