Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.
Apoptosis. 2012 Feb;17(2):174-86. doi: 10.1007/s10495-011-0663-4.
p66Shc, an adaptor molecule which enhances reactive oxygen species (ROS) production by mitochondria, promotes T-cell apoptosis by inducing mitochondrial dysfunction and impairing Ca(2+) homeostasis. We have addressed the potential role of Lck, a kinase which has been implicated in T-cell apoptosis induced by a number of stimuli, in the proapoptotic activity of p66Shc. Lck deficiency in Jurkat T cells overexpressing p66Shc leads to impaired apoptotic responses to supraphysiological increases in Ca(2+). This defect could be rescued by reconstitution of Lck expression, indicating that Lck is required for p66Shc-dependent apoptosis. Furthermore, p66Shc phosphorylation on serine 36 (S36), an event on which the proapoptotic function of p66Shc depends, requires Lck. p66Shc-dependent mitochondrial dysfunction, altered Ca(2+) homeostasis and S36 phosphorylation require moreover the activity of CaMKII, a Ca(2+)/calmodulin-dependent kinase known to be implicated in the proapoptotic activity of Lck in T cells. The results suggest that increases in Ca(2+) lead to CaMKII activation and subsequent Lck-dependent p66Shc phosphorylation on S36. This event causes both mitochondrial dysfunction and impaired Ca(2+) homeostasis, which synergize in promoting Jurkat T-cell apoptosis.
p66Shc 是一种衔接分子，可通过增强线粒体产生的活性氧物种 (ROS) 来促进 T 细胞凋亡，通过诱导线粒体功能障碍和破坏 Ca(2+) 稳态来实现。我们研究了 Lck 的潜在作用，Lck 是一种激酶，它与许多刺激诱导的 T 细胞凋亡有关，在 p66Shc 的促凋亡活性中发挥作用。在过表达 p66Shc 的 Jurkat T 细胞中缺乏 Lck 会导致对超生理 Ca(2+) 增加的凋亡反应受损。通过重建 Lck 的表达可以挽救这种缺陷，表明 Lck 是 p66Shc 依赖性凋亡所必需的。此外，p66Shc 丝氨酸 36 (S36) 的磷酸化依赖于 Lck，这是 p66Shc 促凋亡功能所必需的事件。p66Shc 依赖性线粒体功能障碍、Ca(2+) 稳态改变和 S36 磷酸化还需要 CaMKII 的活性，CaMKII 是一种 Ca(2+)/钙调蛋白依赖性激酶，已知与 T 细胞中 Lck 的促凋亡活性有关。结果表明，Ca(2+) 的增加导致 CaMKII 的激活和随后的 Lck 依赖性 p66Shc 在 S36 上的磷酸化。这一事件导致线粒体功能障碍和 Ca(2+) 稳态受损，协同促进 Jurkat T 细胞凋亡。
