c-Myc Regulates RNA Splicing of the A-Raf Kinase and Its Activation of the ERK Pathway

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 13; pp. 4664 - 4674
• Main Authors: RAUCH, Jens, MORAN-JONES, Kim, ALBRECHT, Valerie, SCHWARZL, Thomas, HUNTER, Keith, GIRES, Olivier, KOLCH, Walter
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2011
• Subjects: Alternative Splicing; Animals; Antineoplastic agents; Biological and medical sciences; Down-Regulation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; HCT116 Cells; HeLa Cells; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - genetics; Heterogeneous-Nuclear Ribonucleoprotein Group F-H - metabolism; Humans; Isoenzymes; MAP Kinase Signaling System; Medical sciences; Mice; NIH 3T3 Cells; Pharmacology. Drug treatments; Proto-Oncogene Proteins A-raf - genetics; Proto-Oncogene Proteins A-raf - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Transformation, Genetic; Tumors; Regulation(control); Splicing; Extracellular signal-regulated protein kinase; RNA; Enzyme; Kinase; Transferases; C-Onc gene; myc Gene; Mitogen-activated protein kinase; Activation; Protooncogene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-4447

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.