Differential regulation of N-Myc and c-Myc synthesis degradation and transcriptional activity by the Ras/MAPK pathway

Myc family proteins, including N-Myc, are key regulators of proliferation and differentiation, with N-Myc overexpression driving neuroblastoma progression. This work investigates how Ras signaling controls N-Myc post-transcriptionally. Findings show Ras activation promotes both N-Myc synthesis and degradation, with translational upregulation outweighing destabilization, resulting in increased protein levels and transcriptional activity. Mechanistic studies reveal Ras-mediated degradation occurs independently of phosphorylation at conserved sites Thr50 and Ser54, indicating distinct regulatory pathways. These insights highlight how hyperactivated Ras enhances N-Myc oncogenic activity and suggest potential therapeutic targets in Ras–N-Myc-driven cancers.