c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway.
Cancer Res
; 71(13): 4664-74, 2011 Jul 01.
Article
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| MEDLINE
| ID: mdl-21512137
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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Base de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas c-myc
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Sistema de Señalización de MAP Quinasas
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Quinasas MAP Reguladas por Señal Extracelular
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Proteínas Proto-Oncogénicas A-raf
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En
Revista:
Cancer Res
Año:
2011
Tipo del documento:
Article