Two distinct pathways leading to nuclear apoptosis.
Two distinct pathways leading to nuclear apoptosis.
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DOI：
10.1084/jem.192.4.571
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发表时间：
2000-08-21
期刊：
影响因子：
--
通讯作者：
Kroemer G
中科院分区：
文献类型：
--
作者：
Susin SA;Daugas E;Ravagnan L;Samejima K;Zamzami N;Loeffler M;Costantini P;Ferri KF;Irinopoulou T;Prévost MC;Brothers G;Mak TW;Penninger J;Earnshaw WC;Kroemer G
Apaf-1−/−或caspase-3−/−细胞经多种凋亡诱导剂处理后，表现出凋亡相关的改变，包括凋亡诱导因子（AIF）从线粒体易位至细胞核、大规模DNA片段化和初始染色质凝聚（I期）。然而，与正常对照细胞相比，Apaf-1−/−或caspase-3−/−细胞未能表现出寡核小体染色质消化和更高级的染色质浓缩模式（II期）。用重组AIF显微注射这些细胞仅引起外周染色质凝聚（阶段I），而用活化的半胱天冬酶-3或其下游靶半胱天冬酶活化的DNA酶（CAD）显微注射引起更明显类型的染色质凝聚（阶段II）。类似地，当添加到纯化的HeLa细胞核中时，AIF导致I期染色质浓缩和大规模DNA片段化，而CAD诱导II期染色质浓缩和寡核小体DNA降解。此外，在无细胞系统中，需要同时中和AIF和CAD以抑制由来自凋亡野生型细胞的细胞质提取物引起的核DNA损失。相比之下，AIF耗竭本身足以抑制凋亡Apaf-1−/−或caspase-3−/−细胞提取物中所含的核DNA丢失。因此，至少有两个冗余的平行途径可能导致细胞凋亡过程中的染色质加工。这些途径之一涉及Apaf-1和半胱天冬酶，以及CAD，并导致寡核小体DNA片段化和高级染色质凝聚。另一个途径，这是半胱天冬酶独立的，涉及AIF，并导致大规模的DNA片段化和外周染色质凝聚。
Apaf-1−/− or caspase-3−/− cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1−/− or caspase-3−/− cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1−/− or caspase-3−/− cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation.
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影响因子：
64.5
作者：
Liu, XS;Zou, H;Wang, XD
通讯作者：
Wang, XD
影响因子：
56.9
作者：
Marzo, I;Brenner, C;Kroemer, G
通讯作者：
Kroemer, G
DOI：
10.1073/pnas.95.23.13618
发表时间：
1998-11-10
影响因子：
11.1
作者：
Zheng, TS;Schlosser, SF;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
10.5
作者：
Woo, M;Hakem, R;Mak, TW
通讯作者：
Mak, TW
影响因子：
64.8
作者：
Enari, M;Sakahira, H;Nagata, S
通讯作者：
Nagata, S