Differential Regulation of N-Myc and c-Myc Synthesis, Degradation, and Transcriptional Activity by the Ras/Mitogen-activated Protein Kinase Pathway

• Published in: The Journal of biological chemistry Vol. 286; no. 44; pp. 38498 - 38508
• Main Authors: Kapeli, Katannya, Hurlin, Peter J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-11-2011; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred C3H; Myc; Neuroblastoma; Plasmids - metabolism; Polyribosomes - metabolism; Polysome; Post-translational Modification; Protein Processing, Post-Translational; Protein Stability; Protein Synthesis and Degradation; Proto-Oncogene Proteins c-myc - metabolism; Ras; ras Proteins - metabolism; Transcription Target Genes; Transcription, Genetic; Translation Control; Post-translational Modification; Ras; Myc; Neuroblastoma; Protein Stability; Transcription Target Genes; Translation Control; Polysome
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.276675

Myc transcription factors are important regulators of proliferation and can promote oncogenesis when deregulated. Deregulated Myc expression in cancers can result from MYC gene amplification and translocation but also from alterations in mitogenic signaling pathways that affect Myc levels through both transcriptional and post-transcription mechanisms. For example, mutations in Ras family GTPase proteins that cause their constitutive activation can increase cellular levels of c-Myc by interfering with its rapid proteasomal degradation. Although enhanced protein stability is generally thought to be applicable to other Myc family members, here we show that c-Myc and its paralog N-Myc respond to oncogenic H-Ras (H-RasG12V) in very different ways. H-RasG12V promotes accumulation of both c-Myc and N-Myc, but although c-Myc accumulation is achieved by enhanced protein stability, N-Myc accumulation is associated with an accelerated rate of translation that overcomes a surprising H-RasG12V-mediated destabilization of N-Myc. We show that H-RasG12V-mediated degradation of N-Myc functions independently of key phosphorylation sites in the highly conserved Myc homology box I region that controls c-Myc protein stability by oncogenic Ras. Finally, we found that N-Myc and c-Myc transcriptional activity is associated with their proteasomal degradation but that N-Myc may be uniquely dependent on Ras-stimulated proteolysis for target gene expression. Taken together, these studies provide mechanistic insight into how oncogenic Ras augments N-Myc levels in cells and suggest that enhanced N-Myc translation and degradation-coupled transactivation may contribute to oncogenesis.
Background: Oncogenic Ras signaling promotes c-Myc accumulation by slowing its degradation.
Results: Unlike c-Myc, oncogenic Ras promotes N-Myc protein degradation but stimulates its accumulation by increasing N-Myc translation.
Conclusion: Ras signaling stimulates N-Myc translation and proteolysis, and Ras-stimulated N-Myc proteolysis correlates with increased N-Myc transcriptional activity.
Significance: Increased N-Myc translation and proteolysis may underlie the oncogenic activity of activated growth factor receptors and Ras.