Rauch, J., Moran-Jones, K., Albrecht, V. et al. (4 more authors) (2011) c-Myc Regulates RNA Splicing of the A-Raf Kinase and Its Activation of the ERK Pathway. Cancer Research, 71 (13). pp. 4664-4674. ISSN 0008-5472
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
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2011 American Association for Cancer Research. This is an author produced version of a paper subsequently published in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | B-RAF; SIGNALING PATHWAYS; PROTEIN-KINASE; CANCER; BINDING; IDENTIFICATION; EXPRESSION; CARCINOMA; MECHANISM; CELLS |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Clinical Dentistry (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 22 Feb 2017 15:30 |
Last Modified: | 22 Mar 2018 23:40 |
Published Version: | https://doi.org/10.1158/0008-5472.CAN-10-4447 |
Status: | Published |
Publisher: | American Association for Cancer Research |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.CAN-10-4447 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:110876 |