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Rauch, J.* ; Moran-Jones, K.* ; Albrecht, V.* ; Schwarzl, T.* ; Hunter, K.* ; Gires, O. ; Kolch, W.

c-Myc regulates RNA splicing of the A-raf kinase and its activation of the ERK pathway.

Cancer Res. 71, 4664-4674 (2011)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords B-raf; Signaling pathways; Protein-kinase; Cancer; Binding; Identification; Expression; Carcinoma; Mechanism; Cells
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Journal Cancer Research
Quellenangaben Volume: 71, Issue: 3, Pages: 4664-4674 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Molecular Oncology (AGV-KON)