Early Events in the Anoikis Program Occur in the Absence of Caspase Activation*
Early Events in the Anoikis Program Occur in the Absence of Caspase Activation*
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失巢凋亡程序中的早期事件发生在缺乏 Caspase 激活的情况下*
DOI：
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发表时间：
2003
影响因子：
4.8
通讯作者：
C. Streuli
中科院分区：
文献类型：
--
作者：
Pengbo Wang;A. Valentijn;A. Gilmore;C. Streuli
许多类型的细胞与细胞外基质的黏附是维持其生存所必需的。在缺乏整合素介导的信号的情况下，正常的上皮细胞经历一种称为失巢凋亡的形式的凋亡。有人认为，启动子caspase的激活是失巢失巢的早期事件，导致Bid裂解和细胞色素c从线粒体释放。我们以前已经证明，乳腺上皮细胞中整合素信号的丢失会导致细胞凋亡，这依赖于Bax从胞浆到线粒体的移位。在这篇文章中，我们问是否需要半胱氨酸天冬氨酸酶来激活Bax以及线粒体内的相关变化。我们发现Bax的激活非常迅速，在失去整合素介导的与细胞外基质的黏附后的15分钟内。与Bax激活相关的构象变化与包括启动子caspase-8在内的caspase无关。我们还检查了凋亡程序中的下游事件，发现细胞色素c的释放至少在延迟1小时后发生，随后激活效应器caspase-3。这种延迟并不是因为需要新的蛋白质合成，因为放线菌酮对Bax的激活、细胞色素c的释放、caspase-3的裂解或细胞凋亡的动力学没有影响。总之，我们的数据表明，乳腺上皮细胞对失巢凋亡的细胞决定发生在缺乏caspase激活的情况下。此外，尽管Bax的构象变化是快速和同步的，但随后的事件是随机发生的，并且具有相当大的延迟。
Adhesion of many cell types to the extracellular matrix is essential to maintain their survival. In the absence of integrin-mediated signals, normal epithelial cells undergo a form of apoptosis termed anoikis. It has been proposed that the activation of initiator caspases is an early event in anoikis, resulting in Bid cleavage and cytochrome c release from mitochondria. We have previously demonstrated that the loss of integrin signaling in mammary epithelial cells results in apoptosis and that this is dependent upon translocation of Bax from the cytosol to the mitochondria. In this paper, we ask whether caspases are required for Bax activation and the associated changes within mitochondria. We show that Bax activation occurs extremely rapidly, within 15 min after loss of integrin-mediated adhesion to extracellular matrix. The conformational changes associated with Bax activation are independent of caspases including the initiator caspase-8. We also examined downstream events in the apoptosis program and found that cytochrome c release occurs after a delay of at least 1 h, with subsequent activation of the effector caspase-3. This delay is not due to a requirement for new protein synthesis, since cycloheximide has no effect on the kinetics of Bax activation, cytochrome c release, caspase-3 cleavage, or apoptosis. Together, our data indicate that the cellular decision for anoikis in mammary epithelial cells occurs in the absence of caspase activation. Moreover, although the conformational changes in Bax are rapid and synchronous, the subsequent events occur stochastically and with considerable delays.
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影响因子：
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