A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells
A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells
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ABT-737 快速诱导细胞凋亡的新范例，涉及原发性白血病和淋巴瘤细胞线粒体外膜破裂
DOI：
--
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发表时间：
2008
影响因子：
12.4
通讯作者：
Gerald M. Cohen
中科院分区：
文献类型：
--
作者：
M. Vogler;David Dinsdale;Xiao;Kenneth W. Young;M. Butterworth;P. Nicotera;Martin J. S. Dyer;Gerald M. Cohen
原代慢性淋巴细胞白血病（CLL）细胞对小分子BCL 2拮抗剂ABT-737非常敏感，ABT-737可诱导细胞凋亡的许多经典生化和超微结构特征，包括BAX/巴克寡聚化、细胞色素c释放、半胱天冬酶激活和染色质凝聚。令人惊讶的是，ABT-737还诱导线粒体内膜透化（MIMP），导致线粒体基质肿胀和线粒体外膜（OMM）破裂，从而允许细胞色素c从线粒体嵴快速流出并促进快速半胱天冬酶活化和细胞凋亡。BAX和巴克似乎参与了OMM不连续性，因为它们定位于OMM断点。值得注意的是，ABT-737在其他原发性B细胞恶性肿瘤中诱导线粒体基质肿胀和OMM不连续，包括套细胞、滤泡和边缘区淋巴瘤细胞，但在研究的几种细胞系中没有。因此，我们描述了一种新的模式，在原发性B细胞恶性肿瘤的细胞凋亡，从而靶向BCL 2的结果在所有经典的功能，细胞凋亡与OMM破裂独立的半胱天冬酶激活。由于大多数用于测量细胞凋亡的方法无法识别这种机制，因此这种机制可能比迄今为止认识到的更为普遍。
Primary chronic lymphocytic leukemia (CLL) cells are exquisitely sensitive to ABT-737, a small molecule BCL2-antagonist, which induces many of the classical biochemical and ultrastructural features of apoptosis, including BAX/BAK oligomerization, cytochrome c release, caspase activation and chromatin condensation. Surprisingly, ABT-737 also induces mitochondrial inner membrane permeabilization (MIMP) resulting in mitochondrial matrix swelling and rupture of the outer mitochondrial membrane (OMM), so permitting the rapid efflux of cytochrome c from mitochondrial cristae and facilitating rapid caspase activation and apoptosis. BAX and BAK appear to be involved in the OMM discontinuities as they localize to the OMM break points. Notably, ABT-737 induced mitochondrial matrix swelling and OMM discontinuities in other primary B-cell malignancies, including mantle cell, follicular and marginal zone lymphoma cells but not in several cell lines studied. Thus, we describe a new paradigm of apoptosis in primary B-cell malignancies, whereby targeting of BCL2 results in all the classical features of apoptosis together with OMM rupture independent of caspase activation. This mechanism may be far more prevalent than hitherto recognized due to the failure of most methods, used to measure apoptosis, to recognize such a mechanism.
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DOI：
10.1152/ajpcell.1997.272.4.c1286
发表时间：
1997-04
期刊：
The American journal of physiology
影响因子：
--
作者：
A. Nieminen;Aaeon M. Byrne;B. Herman;J. Lemasters
通讯作者：
A. Nieminen;Aaeon M. Byrne;B. Herman;J. Lemasters
影响因子：
12.4
作者：
Forte, M.;Bernardi, P.
通讯作者：
Bernardi, P.
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
N. Danial;S. Korsmeyer;H Robert
通讯作者：
N. Danial;S. Korsmeyer;H Robert
影响因子：
50.3
作者：
Konopleva, Marina;Contractor, Rooha;Andreeff, Michael
通讯作者：
Andreeff, Michael
影响因子：
3.5
作者：
He, LH;Lemasters, JJ
通讯作者：
Lemasters, JJ