Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Mol Cell Biol. 2012 Nov;32(22):4523-33. doi: 10.1128/MCB.00774-12. Epub 2012 Sep 4.
The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response.
能够产生适当的防御反应对于生物体在受到致病因素的侵袭时的生存至关重要。然而，允许组织和器官应对这种压力的机制还了解甚少。在这里，我们表明 caspase-3 敲除小鼠或 caspase 抑制剂处理的小鼠在响应各种化学和环境应激（导致晒伤、心肌病或结肠炎）时无法激活抗凋亡 Akt 激酶。在 caspase-3 敲除小鼠中，Akt 激活的缺陷伴随着某些情况下细胞死亡增加和存活能力受损。 RasGAP 的突变导致 caspase-3 无法切割的 RasGAP 纯合子小鼠在 Akt 激活方面表现出类似的缺陷，导致应激器官中的细胞凋亡增加、生理功能明显恶化和疾病发展更强。我们的结果为 caspase-3 作为一种应激强度传感器的相关性提供了证据，该传感器通过启动 RasGAP 切割依赖性的细胞抵抗程序或细胞自杀反应来控制细胞命运。
