Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Oncogene. 2013 Jun 13;32(24):2917-2926. doi: 10.1038/onc.2012.312. Epub 2012 Jul 16.
The Ras/mitogen-activated protein kinase (MAPK) signalling cascade regulates various biological functions, including cell growth, proliferation and survival. As such, this pathway is often deregulated in cancer, including melanomas, which frequently harbour activating mutations in the NRAS and BRAF oncogenes. Hyperactive MAPK signalling is known to promote protein synthesis, but the mechanisms by which this occurs remain poorly understood. Here, we show that expression of oncogenic forms of Ras and Raf promotes the constitutive activation of the mammalian target of rapamycin (mTOR). Using pharmacological inhibitors and RNA interference, we find that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) is partly required for these effects. Using melanoma cell lines carrying activating BRAF mutations, we show that ERK/RSK signalling regulates assembly of the translation initiation complex and polysome formation, as well as the translation of growth-related messenger RNAs containing a 5'-terminal oligopyrimidine (TOP) motif. Accordingly, we find that RSK inhibition abrogates tumour growth in mice. Our findings indicate that RSK may be a valuable therapeutic target for the treatment of tumours characterized by deregulated MAPK signalling, such as melanoma.
Ras/丝裂原活化蛋白激酶（MAPK）信号通路调节着各种生物功能，包括细胞生长、增殖和存活。因此，这条通路在癌症中经常失调，包括黑色素瘤，其中经常存在NRAS 和 BRAF 癌基因的激活突变。已知过度活跃的 MAPK 信号促进蛋白质合成，但这一过程的机制仍知之甚少。在这里，我们表明致癌形式的 Ras 和 Raf 的表达促进了雷帕霉素靶蛋白（mTOR）的组成性激活。通过药理学抑制剂和 RNA 干扰，我们发现 MAPK 激活的蛋白激酶 RSK（p90 核糖体 S6 激酶）部分需要这些作用。使用携带激活 BRAF 突变的黑色素瘤细胞系，我们表明 ERK/RSK 信号调节翻译起始复合物的组装和多核糖体形成，以及含有 5'-末端寡嘧啶（TOP）基序的与生长相关的信使 RNA 的翻译。因此，我们发现 RSK 抑制可消除小鼠肿瘤的生长。我们的研究结果表明，RSK 可能是治疗 MAPK 信号失调的肿瘤的有价值的治疗靶点，例如黑色素瘤。
