MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells

Oncogene. 2012 Mar 15;31(11):1342-53. doi: 10.1038/onc.2011.343. Epub 2011 Aug 8.


The MYCN gene has a critical role in determining the clinical behavior of neuroblastoma. Although it is known that genomic amplification occurs in high-risk subsets, it remains unclear how MYCN expression is regulated in the pathogenesis of neuroblastomas. Here, we report that MYCN expression was regulated by the oncoprotein MDM2 at the post-transcriptional level and was associated with neuroblastoma cell growth. Increasing MDM2 by ectopic overexpression in the cytoplasm enhanced both mRNA and protein expression of MYCN. Mechanistic studies found that the C-terminal RING domain of the MDM2 protein bound to the MYCN mRNA's AREs within the 3'UTR and increased MYCN 3'UTR-mediated mRNA stability and translation. Conversely, MDM2 silencing by specific siRNA rendered the MYCN mRNA unstable and reduced the abundance of the MYCN protein in MYCN-amplified neuroblastoma cell lines. Importantly, this MDM2 silencing resulted in a remarkable inhibition of neuroblastoma cell growth and induction of cell death through a p53-independent pathway. Our results indicate that MDM2 has a p53-independent role in the regulation of both MYCN mRNA stabilization and its translation, suggesting that MDM2-mediated MYCN expression is one mechanism associated with growth of MYCN-associated neuroblastoma and disease progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Cell Death
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic*
  • Genes, p53 / physiology
  • Humans
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / genetics*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / physiology*
  • RNA Interference
  • RNA Stability*
  • RNA, Messenger / biosynthesis
  • Transfection


  • 3' Untranslated Regions
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • RNA, Messenger
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2