Shimoke K, Yamagishi S, Yamada M, Ikeuchi T, Hatanaka H
Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Brain Res Dev Brain Res. 1999 Feb 5;112(2):245-53. doi: 10.1016/s0165-3806(98)00172-2.
Cerebellar granule neurons maintained in medium containing 26 mM potassium or in medium (5 mM potassium) with 50 ng/ml brain-derived neurotrophic factor (BDNF) undergo an apoptotic cell death when exposed to 10 microM LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3-K). To investigate the intracellular signaling mechanism of LY294002-induced apoptosis, the activities of Akt and c-Jun N-terminal kinase (JNK) were measured in cells in HK (26 mM potassium) medium or LK+ (5 mM potassium) medium containing BDNF, with or without 10 microM LY294002. Akt activity decreased following the addition of 10 microM LY294002. In addition, we found that LY294002 increased the JNK activity, which is known to mediate some types of cell death in PNS neurons. We also observed elevated expression of c-Jun by LY294002 in HK+ BDNF. These findings demonstrated that apoptosis induced by inhibition of PI3-K activity involves suppression of the Akt activity and elevation of the JNK activity in cerebellar granule neurons. Our results suggested that the PI3-K-Akt pathway suppresses the activation of JNK and c-Jun expression, and as a result prevents the neuronal cell death in cerebellar granule neurons.
维持在含26 mM钾的培养基中或含50 ng/ml脑源性神经营养因子（BDNF）的培养基（5 mM钾）中的小脑颗粒神经元，在暴露于10 μM磷脂酰肌醇3激酶（PI3-K）抑制剂LY294002时会发生凋亡性细胞死亡。为了研究LY294002诱导凋亡的细胞内信号传导机制，在含有或不含有10 μM LY294002的HK（26 mM钾）培养基或含BDNF的LK +（5 mM钾）培养基中的细胞中测量了Akt和c-Jun氨基末端激酶（JNK）的活性。加入10 μM LY294002后，Akt活性降低。此外，我们发现LY294002增加了JNK活性，已知JNK可介导PNS神经元中的某些类型的细胞死亡。我们还观察到LY294002在HK + BDNF中增加了c-Jun的表达。这些发现表明，PI3-K活性抑制诱导的凋亡涉及小脑颗粒神经元中Akt活性的抑制和JNK活性的升高。我们的结果表明，PI3-K-Akt途径抑制JNK的激活和c-Jun的表达，从而防止小脑颗粒神经元中的神经元细胞死亡。
