Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan, ROC.
Int J Biochem Cell Biol. 2010 Jan;42(1):98-105. doi: 10.1016/j.biocel.2009.09.012. Epub 2009 Sep 25.
In this study, it was shown that the mammalian sterile 20-like serine/threonine protein kinase 3 (Mst3) plays an essential role in the staurosporine-induced apoptosis of HeLa cells. The staurosporine-induced apoptosis was reduced by around 65% by the selective knockdown of Mst3 in stable clones, HeLa(siMst3). Although caspases were shown to be involved in the Mst3-mediated apoptosis, only 15-20% of staurosporine-induced apoptosis was suppressed by the caspase inhibitor, z-DEVD-fmk. Accordingly, Mst3 was proposed to trigger a caspase-independent apoptotic pathway in response to staurosporine. Interestingly, staurosporine greatly induced the mitochondrial membrane potential transition in HeLa cells, but had no effect in Hela(siMst3). The role of Mst3 in controlling the mitochondrial integrity was therefore proposed, presumably through the regulation of Bax. Furthermore, it was shown that staurosporine promoted the nuclear translocation of apoptosis-inducing factor and endonuclease G in HeLa cells. The nuclease activity associated with endonuclease G was also enhanced in response to staurosporine. However, both staurosporine-induced nuclear translocation of apoptosis-inducing factor and endonuclease G and the nuclease activity associated with endonuclease G were markedly reduced in Hela(siMst3). These results suggest that Mst3 may respond to staurosporine to trigger the caspase-independent apoptotic pathway by regulating the nuclear translocation of apoptosis-inducing factor and endonuclease G, and the nuclease activity associated with endonuclease G.
在这项研究中，已经表明哺乳动物 sterile 20 样丝氨酸/苏氨酸蛋白激酶 3（Mst3）在 HeLa 细胞的星形孢菌素诱导的细胞凋亡中发挥重要作用。在稳定克隆中，通过选择性敲低 Mst3，星形孢菌素诱导的细胞凋亡减少了约 65%，HeLa（siMst3）。虽然已经表明半胱天冬酶参与了 Mst3 介导的细胞凋亡，但仅 15-20%的星形孢菌素诱导的细胞凋亡被半胱天冬酶抑制剂 z-DEVD-fmk 抑制。因此，Mst3 被提议在星形孢菌素的作用下触发一种半胱天冬酶非依赖性凋亡途径。有趣的是，星形孢菌素大大诱导了 HeLa 细胞中线粒体膜电位的转变，但在 HeLa（siMst3）中没有影响。因此，Mst3 被提议在控制线粒体完整性方面发挥作用，可能是通过 Bax 的调节。此外，还表明星形孢菌素促进了凋亡诱导因子和内切核酸酶 G 在 HeLa 细胞中的核易位。与内切核酸酶 G 相关的核酸酶活性也在星形孢菌素的作用下增强。然而，星形孢菌素诱导的凋亡诱导因子和内切核酸酶 G 的核易位以及与内切核酸酶 G 相关的核酸酶活性在 HeLa（siMst3）中明显减少。这些结果表明，Mst3 可能通过调节凋亡诱导因子和内切核酸酶 G 的核易位以及与内切核酸酶 G 相关的核酸酶活性来响应星形孢菌素，从而触发半胱天冬酶非依赖性凋亡途径。
