Mackenzie Gerardo G, Oteiza Patricia I
Department of Nutrition, University of California, Davis, Davis California, USA.
J Cell Physiol. 2007 Jan;210(1):246-56. doi: 10.1002/jcp.20861.
Transcription factor NFAT is crucial in the development of the nervous system due to its role in neuronal plasticity and survival. In this study we characterized the role of zinc and the cytoskeleton in the modulation of NFAT in neuronal cells. The incubation of cells in zinc deficient media led to NFAT activation that was inhibited by the calcium chelator BAPTA and the antioxidants (+/-)-alpha-lipoic acid and N-acetyl cysteine, suggesting the involvement of calcium and oxidants in the initial steps of NFAT activation associated with zinc deficiency. At a second step of regulation, a decrease in cellular zinc led to an impaired transport of the active NFAT from the cytosol into the nucleus due to alterations in tubulin polymerization secondary to a decrease in neuronal zinc. Furthermore, disruption of the cytoskeleton structure by cold and chemical agents (colchicine (Col), vinblastine (VB), cytochalasin D (Cyt)) also inhibited NFAT transport into the nucleus. The altered nuclear transport caused a decrease in NFAT-dependent gene expression. This study demonstrates for the first time that zinc can modulate transcription factor NFAT in neuronal cells, and that microtubules are involved in NFAT nuclear translocation, crucial event in the regulation of NFAT transcriptional activity.
转录因子NFAT在神经系统发育中至关重要，因为它在神经元可塑性和存活中发挥作用。在本研究中，我们表征了锌和细胞骨架在神经元细胞中对NFAT调节的作用。在缺锌培养基中培养细胞导致NFAT激活，而这种激活被钙螯合剂BAPTA以及抗氧化剂（±）-α-硫辛酸和N-乙酰半胱氨酸抑制，这表明钙和氧化剂参与了与锌缺乏相关的NFAT激活的初始步骤。在调节的第二步，细胞内锌的减少导致活性NFAT从细胞质向细胞核的转运受损，这是由于神经元锌减少继发微管蛋白聚合改变所致。此外，低温和化学试剂（秋水仙碱（Col）、长春碱（VB）、细胞松弛素D（Cyt））破坏细胞骨架结构也抑制了NFAT向细胞核的转运。核转运改变导致NFAT依赖性基因表达下降。本研究首次证明锌可在神经元细胞中调节转录因子NFAT，并且微管参与NFAT核转位，这是NFAT转录活性调节中的关键事件。
