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首页> 外文期刊>Molecular and Cellular Biology >The Ras/Raf/MEK/Extracellular Signal-Regulated Kinase Pathway Induces Autocrine-Paracrine Growth Inhibition via the Leukemia Inhibitory Factor/JAK/STAT Pathway
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The Ras/Raf/MEK/Extracellular Signal-Regulated Kinase Pathway Induces Autocrine-Paracrine Growth Inhibition via the Leukemia Inhibitory Factor/JAK/STAT Pathway

机译：Ras / Raf / MEK /细胞外信号调节激酶途径通过白血病抑制因子/ JAK / STAT途径诱导自分泌-旁分泌生长抑制

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Sustained activation of the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway can lead to cell cycle arrest in many cell types. We have found, with human medullary thyroid cancer (MTC) cells, that activated Ras or c-Raf-1 can induce growth arrest by producing and secreting an autocrine-paracrine factor. This protein was purified from cell culture medium conditioned by Raf-activated MTC cells and was identified by mass spectrometry as leukemia inhibitory factor (LIF). LIF expression upon Raf activation and subsequent activation of JAK-STAT3 was also observed in small cell lung carcinoma cells, suggesting that this autocrine-paracrine signaling may be a common response to Ras/Raf activation. LIF was sufficient to induce growth arrest and differentiation of MTC cells. This effect was mediated through the gp130/JAK/STAT3 pathway, since anti-gp130 blocking antibody or dominant-negative STAT3 blocked the effects of LIF. Thus, LIF expression provides a novel mechanism allowing Ras/Raf signaling to activate the JAK-STAT3 pathway. In addition to this cell-extrinsic growth inhibitory pathway, we find that the Ras/Raf/MEK/ERK pathway induces an intracellular growth inhibitory signal, independent of the LIF/JAK/STAT3 pathway. Therefore, activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest and differentiation via at least two different signaling pathways. This use of multiple pathways may be important for “fail-safe” induction and maintenance of cell cycle arrest.
机译：Ras / Raf / MEK /细胞外信号调节激酶（ERK）途径的持续激活可以导致许多细胞类型的细胞周期停滞。我们发现，对于人类甲状腺髓样癌（MTC）细胞，活化的Ras或c-Raf-1可以通过产生和分泌自分泌旁分泌因子来诱导生长停滞。从经Raf激活的MTC细胞调节的细胞培养基中纯化该蛋白，并通过质谱鉴定为白血病抑制因子（LIF）。在小细胞肺癌细胞中，还观察到Raf激活后JAF-STAT3激活后的LIF表达，这表明这种自分泌-旁分泌信号传导可能是对Ras / Raf激活的常见反应。 LIF足以诱导MTC细胞的生长停滞和分化。此作用是通过gp130 / JAK / STAT3途径介导的，因为抗gp130阻断抗体或显性负STAT3阻断了LIF的作用。因此，LIF表达提供了一种新颖的机制，允许Ras / Raf信号激活JAK-STAT3途径。除了此细胞外在生长抑制途径，我们发现Ras / Raf / MEK / ERK途径诱导细胞内生长抑制信号，独立于LIF / JAK / STAT3途径。因此，Ras / Raf / MEK / ERK途径的激活可以通过至少两种不同的信号传导途径导致生长停滞和分化。多种途径的使用对于“故障安全”诱导和维持细胞周期停滞可能很重要。

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