Namgung U, Xia Z
Toxicology Program, Department of Environmental Health, and Graduate Programs in Neurobiology and Behavior and Molecular and Cell Biology, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2000 Sep 1;20(17):6442-51. doi: 10.1523/JNEUROSCI.20-17-06442.2000.
c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase are activated by stress and are implicated in regulation of apoptosis in several tissues. However, their contribution to stress-induced apoptosis in CNS neurons is not well defined. Here we investigated the role of JNK and p38 in cortical neuron apoptosis caused by sodium arsenite treatment. Sodium arsenite is an environmental toxicant that causes developmental defects in the CNS. Treatment of cortical neurons with sodium arsenite activated p38 and JNK3 but not JNK1 or JNK2. It also induced c-Jun phosphorylation. Furthermore, sodium arsenite induced cortical neuron apoptosis. This apoptosis was attenuated by SB203580, an inhibitor of p38, and by CEP-1347, an inhibitor of JNK activation. Expression of dominant-interfering mutants of the JNK or p38 pathways inhibited apoptosis induced by arsenite, whereas expression of constitutive active mutants for either pathway induced apoptosis. Moreover, the caspase inhibitor zVAD-fluoromethylketone as well as expression of bcl-2 or bcl-xL inhibited cortical neuron apoptosis induced by arsenite or by constitutive activation of JNK or p38. These data indicate that both JNK and p38 contribute to arsenite-induced apoptosis in primary CNS neurons, and this apoptosis requires the bcl-2-caspase pathway. This is the first evidence that a specific JNK isoform is differentially activated by stress and contributes to neuronal apoptosis.
c-Jun氨基末端蛋白激酶（JNK）和p38丝裂原活化蛋白激酶可被应激激活，并参与多种组织中细胞凋亡的调控。然而，它们在中枢神经系统（CNS）神经元应激诱导的细胞凋亡中的作用尚未明确界定。在此，我们研究了JNK和p38在亚砷酸钠处理所致皮质神经元凋亡中的作用。亚砷酸钠是一种环境毒物，可导致中枢神经系统发育缺陷。用亚砷酸钠处理皮质神经元可激活p38和JNK3，但不激活JNK1或JNK2。它还诱导c-Jun磷酸化。此外，亚砷酸钠诱导皮质神经元凋亡。p38抑制剂SB203580和JNK激活抑制剂CEP-1347可减弱这种凋亡。JNK或p38信号通路显性干扰突变体的表达可抑制亚砷酸盐诱导的凋亡，而任一信号通路组成型活性突变体的表达则诱导凋亡。此外，半胱天冬酶抑制剂zVAD-氟甲基酮以及bcl-2或bcl-xL的表达可抑制亚砷酸盐或JNK或p38组成型激活诱导的皮质神经元凋亡。这些数据表明，JNK和p38均参与了原代中枢神经系统神经元中亚砷酸盐诱导的凋亡，且这种凋亡需要bcl-2-半胱天冬酶信号通路。这是首个表明特定JNK亚型可被应激差异激活并参与神经元凋亡的证据。
