title: c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway.
abstract: A-Raf kinase can inhibit apoptosis by binding to the proapoptotic mammalian sterile 20-like kinase (MST2). This function relies on expression of hnRNP H, which ensures the correct splicing of a-raf mRNA needed to produce full-length A-Raf protein. Here, we showed that expression of hnRNP H and production of full-length A-Raf is positively controlled by c-Myc. Low c-Myc reduces hnRNP H expression and switches a-raf splicing to produce A-Raf(short), a truncated protein. Importantly, A-Raf(short) fails to regulate MST2 but retains the Ras-binding domain such that it functions as a dominant negative mutant suppressing Ras activation and transformation. Human colon and head and neck cancers exhibit high hnRNP H and high c-Myc levels resulting in enhanced A-Raf expression and reduced expression of A-Raf(short). Conversely, in normal cells and tissues in which c-Myc and hnRNP H are low, A-Raf(short) suppresses extracellular signal regulated kinase activation such that it may act as a safeguard against oncogenic transformation. Our findings offered a new paradigm to understand how c-Myc coordinates diverse cell functions by directly affecting alternate splicing of key signaling components.
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin, Ireland.
authors.forename: Jens
authors.initials: J
authors.lastname: Rauch
authors.forename: Kim
authors.initials: K
authors.lastname: Moran-Jones
authors.forename: Valerie
authors.initials: V
authors.lastname: Albrecht
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzl
authors.forename: Keith
authors.initials: K
authors.lastname: Hunter
authors.forename: Olivier
authors.initials: O
authors.lastname: Gires
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D045325:HCT116 Cells; D006367:HeLa Cells; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D014170:Transformation, Genetic; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D007527:Isoenzymes; D016271:Proto-Oncogene Proteins c-myc; D048491:Proto-Oncogene Proteins A-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins