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

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.

• 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)
• 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

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)