黑色素瘤中重新连接的ERK-JNK信号通路。
Rewired ERK-JNK signaling pathways in melanoma.
作者信息
Lopez-Bergami Pablo, Huang Conway, Goydos James S, Yip Dana, Bar-Eli Menashe, Herlyn Meenhard, Smalley Keiran S M, Mahale Alka, Eroshkin Alexey, Aaronson Stuart, Ronai Ze'ev
机构信息
Signal Transduction Program, The Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
出版信息
Cancer Cell. 2007 May;11(5):447-60. doi: 10.1016/j.ccr.2007.03.009.
Abstract
Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun increases transcription of target genes, including RACK1, an adaptor protein that enables PKC to phosphorylate and enhance JNK activity, enforcing a feed-forward mechanism of the JNK-Jun pathway. Activated c-Jun is also responsible for elevated cyclin D1 expression, which is frequently overexpressed in human melanoma. Our data reveal that, in human melanoma, the rewired ERK signaling pathway upregulates JNK and activates the c-Jun oncogene and its downstream targets, including RACK1 and cyclin D1.
摘要
MEK-ERK信号通路的组成性激活在黑色素瘤中经常被发现。在此，我们确定了一种在人类黑色素瘤中将ERK与JNK信号通路联系起来的机制。组成性激活的ERK分别通过CREB和GSK3增加c-Jun的转录和稳定性。随后，c-Jun增加包括RACK1在内的靶基因的转录，RACK1是一种衔接蛋白，可使PKC磷酸化并增强JNK活性，从而强化JNK-Jun信号通路的前馈机制。激活的c-Jun还导致细胞周期蛋白D1表达升高，该蛋白在人类黑色素瘤中经常过度表达。我们的数据表明，在人类黑色素瘤中，重新布线的ERK信号通路上调JNK并激活c-Jun癌基因及其下游靶点，包括RACK1和细胞周期蛋白D1。
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