Rewired ERK-JNK signaling pathways in melanoma
Rewired ERK-JNK signaling pathways in melanoma
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DOI：
10.1016/j.ccr.2007.03.009
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发表时间：
2007-05-01
期刊：
影响因子：
50.3
通讯作者：
Ronai, Ze'ev
中科院分区：
文献类型：
--
作者：
Lopez-Bergami, Pablo;Huang, Conway;Ronai, Ze'ev
MEK-ERK 信号传导的组成型激活常见于黑色素瘤中。在这里，我们确定了人类黑色素瘤中将 ERK 与 JNK 信号传导联系起来的机制。组成型活性 ERK 增加 c-Jun 转录和稳定性，这分别由 CREB 和 GSK3 介导。随后，c-Jun 增加靶基因的转录，包括 RACK1，一种接头蛋白，使 PKC 能够磷酸化并增强 JNK 活性，从而强化 JNK-Jun 通路的前馈机制。激活的 c-Jun 还导致细胞周期蛋白 131 表达升高，而细胞周期蛋白 131 在人类黑色素瘤中经常过度表达。我们的数据显示，在人类黑色素瘤中，重新连接的 ERK 信号通路上调 JNK 并激活 c-Jun 癌基因及其下游靶标，包括 RACK1 和细胞周期蛋白 D1。
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 131 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.