유전자 적중법을 통한 JIP1의 억제가 국소 허혈 뇌의 신경세포에 미치는 영향

초록

JIP1 (also called IB1) functions as a scaffold protein organizing the components of JNK pathway and, when overexpressed, produces cytoprotective effects in various cell lines. A missense mutation of JIP1/IB1 (S59N) in human reduced the ability of JIP1 to suppress apoptosis and the function of JNK pathway on the INS (encoding insulin) gene transcription. However, the roles of JIP1 in the brain have not been established in detail. To unravel the in vivo functions of JIP1/IB1, we generated mice lacking the jip1 gene by homologous recombination. The basal activity of JNK in the brain of jip1+/- and jip1-/- was maintained as similarly as that in normal brain of jip1+/+. Transient focal ischemic insult produced by middle cerebral artery occlusion (MCAO)/reperfusion induced a large increase of phospho-JNK in the brain of jip1+/+, jip1+/-, and jip1-/-. Unlike that in jip1+/+ or jip1+/-, however, the surge of phosphorylated JNK in the post-ischemic brain was rapidly repressed in jip1-/-. In parallel, the MCAO/reperfusion-induced cell death occurred in the brain of jip1+/+ and jip1+/- was profoundly suppressed in jip1-/-. These results suggest that the precise balance of JIP1/IB1 plays a crucial role in the maintenance of phosphorylated forms of JNK and in neuronal survival in ischemic brain, but JIP1/IB1 is not essential for JNK activation.