M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells.
M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells.
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DOI：
10.1002/jcb.23458
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发表时间：
2012-04
影响因子：
4
通讯作者：
Quilliam, Lawrence A.
中科院分区：
文献类型：
--
作者：
Castro, Ariel F.;Campos, Tania;Babcock, Justin T.;Armijo, Marisol E.;Martinez-Conde, Alfonso;Pincheira, Roxana;Quilliam, Lawrence A.
先前有报道称M-Ras的组成性激活引起小鼠细胞的形态和生长转变，这表明M-Ras在肿瘤发生中起作用。M-Ras的细胞转化与Raf/MEK/ERK通路的弱激活相关，尽管其他下游效应物也有贡献。最近的研究表明，不同于Raf/MEK/ERK级联的信号事件对人类肿瘤的发生至关重要。然而，目前尚不清楚M-Ras在人类细胞中触发了哪些信号事件。利用在其效应结合环中含有额外突变的组成型活性M-Ras (Q71L)，我们发现M-Ras在人MCF-7乳腺癌细胞中诱导MEK/ erk依赖性和非依赖性的Elk1激活以及PI3K/Akt和JNK/cJun激活。在研究的几种人类细胞系中，M-Ras诱导的MEK/ erk独立的Elk1激活仅在MCF-7细胞中检测到，并且与Rlf /M-Ras相互作用和Ral /JNK激活相关。EGF支持M-Ras信号在乳腺癌中的作用，激活M-Ras并促进其与内源性Rlf的相互作用。此外，M-Ras的组成性激活诱导了依赖PI3K/Akt、MEK/ERK和JNK激活的不依赖雌激素的MCF-7细胞生长。因此，我们的研究表明，M-Ras信号活动在人类细胞之间是不同的，这突出了在每种细胞类型中定义Ras蛋白信号的重要性，特别是在设计Ras诱导癌症的治疗方法时。这些发现还表明，M-Ras活性可能对egfr依赖性肿瘤的进展很重要。
Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as PI3K/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf /M-Ras interaction and Ral /JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors.
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