Casciati Arianna, Ferri Alberto, Cozzolino Mauro, Celsi Fulvio, Nencini Monica, Rotilio Giuseppe, Carrì Maria Teresa
Fondazione S. Lucia IRCCS, Rome, Italy.
J Neurochem. 2002 Dec;83(5):1019-29. doi: 10.1046/j.1471-4159.2002.01232.x.
Previous evidence supports the notion of a redox regulation of protein phosphatase calcineurin that might be relevant for neurodegenerative processes where an imbalance between generation and removal of reactive oxygen species occurs. We have recently observed that calcineurin activity is depressed in human neuroblastoma cells expressing Cu,Zn superoxide dismutase (SOD1) mutant G93A and in brain areas from G93A transgenic mice, and that mutant G93A-SOD1 oxidatively inactivates calcineurin in vitro. We have studied the possibility that, by interfering directly with calcineurin activity, mutant SOD1 can modulate pathways of signal transduction mediated by redox-sensitive transcription factors. In this paper, we report a calcineurin-dependent activation of nuclear factor-kappaB (NF-kappaB) induced by the expression of familial amyotrophic lateral sclerosis (fALS)-SOD1s in human neuroblastoma cell lines. Alteration of the phosphorylation state of IkappaBalpha (the inhibitor of NF-kappaB translocation into the nucleus) and induction of cyclooxygenase 2 are consistent with the up-regulation of this transcription factor in this system. All of these modifications might be relevant to signaling pathways involved in the pathogenesis of fALS.
先前的证据支持蛋白磷酸酶钙调神经磷酸酶存在氧化还原调节的观点，这可能与神经退行性过程相关，在这些过程中活性氧的产生和清除之间会出现失衡。我们最近观察到，在表达铜锌超氧化物歧化酶（SOD1）突变体G93A的人神经母细胞瘤细胞以及G93A转基因小鼠的脑区中，钙调神经磷酸酶的活性受到抑制，并且突变体G93A-SOD1在体外可氧化使钙调神经磷酸酶失活。我们研究了突变体SOD1通过直接干扰钙调神经磷酸酶的活性来调节由氧化还原敏感转录因子介导的信号转导途径的可能性。在本文中，我们报道了在人神经母细胞瘤细胞系中，家族性肌萎缩侧索硬化症（fALS）-SOD1的表达诱导了一种依赖钙调神经磷酸酶的核因子κB（NF-κB）激活。IκBα（NF-κB转位到细胞核中的抑制剂）磷酸化状态的改变以及环氧合酶2的诱导与该系统中这种转录因子的上调一致。所有这些修饰可能与fALS发病机制中涉及的信号通路有关。
