Canellada Andrea, Cano Eva, Sánchez-Ruiloba Lucía, Zafra Francisco, Redondo Juan Miguel
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CBM-CSIC), Universidad Autónoma de Madrid (UAM), Facultad de Ciencias, Madrid 28049, Spain.
Mol Cell Neurosci. 2006 Apr;31(4):692-701. doi: 10.1016/j.mcn.2005.12.008. Epub 2006 Feb 2.
We report induction of TNF-alpha via the calcium/calcineurin/NFAT pathway in PC12 neural cells. In PC12, expression of TNF-alpha mRNA, protein and TNF-alpha gene promoter activity was induced by co-stimulation with phorbol ester and either calcium ionophore A23187 or the L-type Voltage Gated Calcium Channel agonist Bay K 8644. Pre-treatment with calcineurin inhibitors CsA or FK506 inhibited the dominant calcium-dependent component of this induction, limiting it to the level achieved with phorbol ester alone. Promoter activation by Bay was abolished by nifedipine, a specific inhibitor of L-type Voltage Gated Calcium Channels. Exogenous NFAT protein transactivated the TNF-alpha promoter, and the peptide VIVIT-a specific inhibitor of calcineurin/NFAT binding-blocked calcium-inducible transactivation of the TNF-alpha promoter. Given proposed functions of TNF-alpha in spatial learning, memory and the pathogenesis of neurodegenerative diseases, the data presented suggest an important role for calcineurin/NFAT signaling in these key neurological processes.
我们报道了在PC12神经细胞中通过钙/钙调神经磷酸酶/NFAT途径诱导肿瘤坏死因子-α（TNF-α）。在PC12细胞中，佛波酯与钙离子载体A23187或L型电压门控钙通道激动剂Bay K 8644共同刺激可诱导TNF-α mRNA、蛋白表达及TNF-α基因启动子活性。用钙调神经磷酸酶抑制剂环孢素A（CsA）或他克莫司（FK506）预处理可抑制这种诱导的主要钙依赖性成分，使其限制在仅用佛波酯所达到的水平。L型电压门控钙通道的特异性抑制剂硝苯地平可消除Bay对启动子的激活作用。外源性NFAT蛋白可反式激活TNF-α启动子，而肽VIVIT（钙调神经磷酸酶/NFAT结合的特异性抑制剂）可阻断TNF-α启动子的钙诱导反式激活。鉴于TNF-α在空间学习、记忆及神经退行性疾病发病机制中的假定功能，本文所呈现的数据表明钙调神经磷酸酶/NFAT信号在这些关键神经过程中起重要作用。
