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

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Title: c-Myc Regulates RNA Splicing of the A-Raf Kinase and Its Activation of the ERK Pathway
Authors: Rauch, Jens
Moran-Jones, K.
Albrecht, V.
et al.
Permanent link: http://hdl.handle.net/10197/5079
Date: 21-Apr-2011
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-Rafshort, a truncated protein. Importantly, A-Rafshort 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-Rafshort. Conversely, in normal cells and tissues in which c-Myc and hnRNP H are low, A-Rafshort 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.
Type of material: Journal Article
Publisher: American Association for Cancer Research
Journal: Cancer Research
Volume: 71
Issue: 13
Start page: 4664
End page: 4674
Copyright (published version): 2011 American Association for Cancer Research
Keywords: c-MycRNA SplicingA-Raf Kinase
DOI: 10.1158/0008-5472.CAN-10-4447
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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