UMR 892 INSERM/6299 CNRS/Université de Nantes, Team 8 Cell survival and tumor escape in breast cancer, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France.
Cell Death Differ. 2013 May;20(5):755-64. doi: 10.1038/cdd.2013.6. Epub 2013 Feb 22.
Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa.
虽然 Bcl-2 家族成员通过调节线粒体通透性来控制半胱天冬酶的活性，但半胱天冬酶也可以通过尚未明确的机制在线粒体上游放大细胞凋亡过程。我们在此表明，用一种强效的 Bcl-2 和 Bcl-xL 抑制剂 ABT-737 处理会触发 BH3 仅蛋白、Mcl-1 抑制剂 Noxa 的 caspase 依赖性诱导。RNA 干扰实验表明，Noxa 的诱导和随后的细胞死亡不仅依赖于转录因子 E2F-1，还依赖于其调节剂 pRb。在对 ABT-737 的反应中，pRb 被半胱天冬酶切割成一种仍与 E2F-1 相互作用的 p68Rb 形式。此外，pRb 与 E2F-1 一起占据 noxa 启动子，在 ABT-737 处理时以 caspase 依赖性方式。因此，半胱天冬酶通过将 Mcl-1 的抑制与 Bcl-2/Bcl-xL 的抑制相偶联，通过 pRb/E2F-1 依赖性诱导 Noxa 来促进线粒体凋亡途径的触发。
