Gourlay C W, Ayscough K R
Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, United Kingdom.
Mol Cell Biol. 2006 Sep;26(17):6487-501. doi: 10.1128/MCB.00117-06.
Recent research has revealed a conserved role for the actin cytoskeleton in the regulation of aging and apoptosis among eukaryotes. Here we show that the stabilization of the actin cytoskeleton caused by deletion of Sla1p or End3p leads to hyperactivation of the Ras signaling pathway. The consequent rise in cyclic AMP (cAMP) levels leads to the loss of mitochondrial membrane potential, accumulation of reactive oxygen species (ROS), and cell death. We have established a mechanistic link between Ras signaling and actin by demonstrating that ROS production in actin-stabilized cells is dependent on the G-actin binding region of the cyclase-associated protein Srv2p/CAP. Furthermore, the artificial elevation of cAMP directly mimics the apoptotic phenotypes displayed by actin-stabilized cells. The effect of cAMP elevation in inducing actin-mediated apoptosis functions primarily through the Tpk3p subunit of protein kinase A. This pathway represents the first defined link between environmental sensing, actin remodeling, and apoptosis in Saccharomyces cerevisiae.
最近的研究揭示了肌动蛋白细胞骨架在真核生物衰老和凋亡调控中的保守作用。在此我们表明，缺失Sla1p或End3p导致的肌动蛋白细胞骨架稳定会导致Ras信号通路的过度激活。由此导致的环磷酸腺苷（cAMP）水平升高会导致线粒体膜电位丧失、活性氧（ROS）积累以及细胞死亡。通过证明肌动蛋白稳定细胞中的ROS产生依赖于环化酶相关蛋白Srv2p/CAP的G-肌动蛋白结合区域，我们建立了Ras信号与肌动蛋白之间的机制联系。此外，cAMP的人工升高直接模拟了肌动蛋白稳定细胞所表现出的凋亡表型。cAMP升高诱导肌动蛋白介导的凋亡的作用主要通过蛋白激酶A的Tpk3p亚基发挥。该途径代表了酿酒酵母中环境感知、肌动蛋白重塑和凋亡之间的首个明确联系。
