Bonny C, Oberson A, Steinmann M, Schorderet D F, Nicod P, Waeber G
Division of Medical Genetics and the Department of Internal Medicine, CHUV University Hospital, 1011 Lausanne Switzerland.
J Biol Chem. 2000 Jun 2;275(22):16466-72. doi: 10.1074/jbc.M908297199.
IB1/JIP-1 is a scaffold protein that interacts with upstream components of the c-Jun N-terminal kinase (JNK) signaling pathway. IB1 is expressed at high levels in pancreatic beta cells and may therefore exert a tight control on signaling events mediated by JNK in these cells. Activation of JNK by interleukin 1 (IL-1beta) or by the upstream JNK constitutive activator DeltaMEKK1 promoted apoptosis in two pancreatic beta cell lines and decreased IB1 content by 50-60%. To study the functional consequences of the reduced IB1 content in beta cell lines, we used an insulin-secreting cell line expressing an inducible IB1 antisense RNA that lead to a 38% IB1 decrease. Reducing IB1 levels in these cells increased phosphorylation of c-Jun and increased the apoptotic rate in presence of IL-1beta. Nitric oxide production was not stimulated by expression of the IB1 antisense RNA. Complementary experiments indicated that overexpression of IB1 in insulin-producing cells prevented JNK-mediated activation of the transcription factors c-Jun, ATF2, and Elk1 and decreased IL-1beta- and DeltaMEKK1-induced apoptosis. These data indicate that IB1 plays an anti-apoptotic function in insulin-producing cells probably by controlling the activity of the JNK signaling pathway.
IB1/JIP-1是一种支架蛋白，可与c-Jun氨基末端激酶（JNK）信号通路的上游成分相互作用。IB1在胰腺β细胞中高水平表达，因此可能对这些细胞中由JNK介导的信号事件进行严格控制。白细胞介素1（IL-1β）或上游JNK组成型激活剂DeltaMEKK1激活JNK，可促进两种胰腺β细胞系的凋亡，并使IB1含量降低50%-60%。为了研究β细胞系中IB1含量降低的功能后果，我们使用了一种表达可诱导性IB1反义RNA的胰岛素分泌细胞系，该细胞系导致IB1降低了38%。降低这些细胞中的IB1水平会增加c-Jun的磷酸化，并在存在IL-1β的情况下增加凋亡率。IB1反义RNA的表达未刺激一氧化氮的产生。补充实验表明，在胰岛素产生细胞中过表达IB1可阻止JNK介导的转录因子c-Jun、ATF2和Elk1的激活，并降低IL-1β和DeltaMEKK1诱导的凋亡。这些数据表明，IB1可能通过控制JNK信号通路的活性，在胰岛素产生细胞中发挥抗凋亡功能。
