Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Transformation, Neoplastic
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Enzyme Activation / drug effects
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Eukaryotic Initiation Factor-4F / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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MAP Kinase Signaling System* / drug effects
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Mechanistic Target of Rapamycin Complex 1
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Melanoma / enzymology
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Melanoma / metabolism*
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Melanoma / pathology*
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Mice
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Multiprotein Complexes / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins B-raf / metabolism*
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 90-kDa / deficiency
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Ribosomal Protein S6 Kinases, 90-kDa / genetics
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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TOR Serine-Threonine Kinases / metabolism*
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raf Kinases / metabolism
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ras Proteins / metabolism
Substances
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Eukaryotic Initiation Factor-4F
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Multiprotein Complexes
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Protein Kinase Inhibitors
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RNA, Messenger
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BRAF protein, human
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins B-raf
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Ribosomal Protein S6 Kinases, 90-kDa
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TOR Serine-Threonine Kinases
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raf Kinases
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Extracellular Signal-Regulated MAP Kinases
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ras Proteins