Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells.
Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells.
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DOI：
10.1101/gad.267997.115
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发表时间：
2015-10-15
影响因子：
10.5
通讯作者：
Kaufmann SH
中科院分区：
文献类型：
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作者：
Dai H;Ding H;Meng XW;Peterson KL;Schneider PA;Karp JE;Kaufmann SH
在这项研究中，戴等人。表明促凋亡 BCL2 家族成员 BAK 的浓度依赖性自动激活在控制内在凋亡中发挥重要作用。这些发现提供了对 BAK 寡聚化的新见解，并证明了应用这一新知识如何提高淋巴造血细胞对各种死亡刺激的敏感性。线粒体外膜透化（MOMP）是内在凋亡途径的关键步骤，目前尚不完全清楚。目前的模型强调 BH3-only BCL2 家族成员在 BAX 和 BAK 激活中的作用。在这里，我们证明了无细胞条件下浓度依赖性 BAK 自激活，并提供了证据表明这种自激活在调节完整细胞的内在凋亡途径中发挥着关键作用。特别是，我们发现，在没有外源性死亡刺激的情况下，淋巴造血细胞系中高达 80% 的 BAK（但不是 BAX）发生寡聚化并与抗凋亡 BCL2 家族成员结合。这种组成性 BAK 寡聚化的程度会因 BAK 敲低而减弱，并且不受 BIM 或 PUMA 下调的影响。进一步分析表明，细胞对BH3模拟物的敏感性反映了BAK组成性结合的抗凋亡蛋白的特性，广泛的BCLXL•BAK复合物预测navitoclax敏感性，广泛的MCL1•BAK复合物预测A1210477敏感性。此外，高 BAK 表达与临床急性髓性白血病对化疗的敏感性相关，而低 BAK 水平与耐药和复发相关。总的来说，这些结果为目前对 MOMP 的理解提供了信息，并为 BH3 模拟物在不直接激活 BAX 或 BAK 的情况下诱导细胞凋亡的能力提供了新的见解。
In this study, Dai et al. show that concentration-dependent autoactivation of the proapoptotic BCL2 family member BAK plays an important role in the control of intrinsic apoptosis. These findings provides novel insight into BAK oligomerization and demonstrate how applying this new knowledge can result in sensitivity of lymphohematopoietic cells to various death stimuli. Mitochondrial outer membrane permeabilization (MOMP), a key step in the intrinsic apoptotic pathway, is incompletely understood. Current models emphasize the role of BH3-only BCL2 family members in BAX and BAK activation. Here we demonstrate concentration-dependent BAK autoactivation under cell-free conditions and provide evidence that this autoactivation plays a key role in regulating the intrinsic apoptotic pathway in intact cells. In particular, we show that up to 80% of BAK (but not BAX) in lymphohematopoietic cell lines is oligomerized and bound to anti-apoptotic BCL2 family members in the absence of exogenous death stimuli. The extent of this constitutive BAK oligomerization is diminished by BAK knockdown and unaffected by BIM or PUMA down-regulation. Further analysis indicates that sensitivity of cells to BH3 mimetics reflects the identity of the anti-apoptotic proteins to which BAK is constitutively bound, with extensive BCLXL•BAK complexes predicting navitoclax sensitivity, and extensive MCL1•BAK complexes predicting A1210477 sensitivity. Moreover, high BAK expression correlates with sensitivity of clinical acute myelogenous leukemia to chemotherapy, whereas low BAK levels correlate with resistance and relapse. Collectively, these results inform current understanding of MOMP and provide new insight into the ability of BH3 mimetics to induce apoptosis without directly activating BAX or BAK.