Up-regulation of SEPT9_v1 stabilizes c-Jun-N-Terminal kinase and contributes to its pro-proliferative activity in mammary epithelial cells
Up-regulation of SEPT9_v1 stabilizes c-Jun-N-Terminal kinase and contributes to its pro-proliferative activity in mammary epithelial cells
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DOI：
10.1016/j.cellsig.2008.11.007
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发表时间：
2009-04-01
影响因子：
4.8
通讯作者：
Petty, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Gonzalez, Maria E.;Makarova, Olga;Petty, Elizabeth M.
SEPT9_v1是septin基因家族成员SEPT 9的最大转录物，编码与乳腺上皮细胞的致瘤性转化有关的septin同种型。在两种乳腺癌细胞系、原发性乳腺癌以及其他实体瘤恶性肿瘤中也观察到高水平的SEM_vI表达。我们发现SEPT9_v1和c-Jun-N-末端激酶（JNK）之间存在一种新的相互作用，JNK是一种在细胞应激反应、细胞增殖和细胞存活中重要的促分裂原活化蛋白激酶。我们发现SEM_v1的上调通过延迟JNK的降解来稳定JNK，从而激活JNK转录组。与对照组相比，表达SEPT9_v1的乳腺上皮细胞中的C-jun激酶测定显示JNK/c-Jun转录活性增加。这种增加与细胞周期蛋白D1的水平增加有关，细胞周期蛋白D1是许多细胞类型中通过G细胞周期进展所需的增殖反应的关键组分。这些发现证明了septin蛋白和JNK信号通路之间的第一个联系。重要的是，它表明了SEM_v1在驱动乳腺上皮细胞增殖中的新功能作用，这是与乳腺癌直接相关的肿瘤发生的标志性特征。(C)2008年由Elsevier Inc.出版
SEPT9_v1, the largest transcript of the septin gene family member, SEPT9, encodes a septin isoform implicated in the tumorigenic transformation of mammary epithelial cells. High levels of SEM_vI expression also have been observed in both breast cancer cell lines, primary breast cancers as well as other solid tumor malignancies. We found a novel interaction between SEPT9_v1 and the c-Jun-N-terminal kinase (JNK), a mitogen-activated protein kinase important in cellular stress responses, cell proliferation, and cell survival. We found that up-regulation of SEM_v1 stabilizes JNK by delaying its degradation, thereby activating the JNK transcriptome. C-jun kinase assays in mammary epithelial cells expressing SEPT9_v1, compared to controls, exhibited increased JNK/c-Jun transcriptional activity. This increase was associated with increased levels of cyclin D1, a critical component of the proliferative response required for progression through G, of the cell cycle in many cell types. These findings demonstrate the first link between a septin protein and the JNK signaling pathway. Importantly, it suggests a novel functional role of SEM_v1 in driving cellular proliferation of mammary epithelial cells, a hallmark feature of oncogenesis that is directly relevant to breast cancer. (C) 2008 Published by Elsevier Inc.