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.
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Authors | Jens Rauch, Kim Moran-Jones, Valerie Albrecht, Thomas Schwarzl, Keith Hunter, Olivier Gires, Walter Kolch |
Journal | Cancer research
(Cancer Res)
Vol. 71
Issue 13
Pg. 4664-74
(Jul 01 2011)
ISSN: 1538-7445 [Electronic] United States |
PMID | 21512137
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2011 AACR. |
Chemical References |
- Heterogeneous-Nuclear Ribonucleoprotein Group F-H
- Isoenzymes
- Proto-Oncogene Proteins c-myc
- Proto-Oncogene Proteins A-raf
- Extracellular Signal-Regulated MAP Kinases
- ras Proteins
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Topics |
- Alternative Splicing
- Animals
- Down-Regulation
- Enzyme Activation
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- HCT116 Cells
- HeLa Cells
- Heterogeneous-Nuclear Ribonucleoprotein Group F-H
(genetics, metabolism)
- Humans
- Isoenzymes
- MAP Kinase Signaling System
- Mice
- NIH 3T3 Cells
- Proto-Oncogene Proteins A-raf
(genetics, metabolism)
- Proto-Oncogene Proteins c-myc
(genetics, metabolism)
- Transformation, Genetic
- ras Proteins
(genetics, metabolism)
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