MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells

• Type of Material: Article
• Authors: Lubing Gu, Emory University; Hailong Zhang, Emory University; Jing He, Emory University; Jiansha Li, Emory University; Mei Huang, Emory University; Muxiang Zhou, Emory University
• Language: English
• Date: 2012-03-15
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Macmillan Publishers Limited
• Final Published Version (URL): http://www.nature.com/onc/journal/v31/n11/full/onc2011343a.html
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 31
• Issue: 11
• Start Page: 1342
• End Page: 1353
• Grant/Funding Information: This work was supported by the National Institutes of Health (R01 CA123490, R01CA143107 to MZ) and CURE (MZ and LG).
• Research Categories: Health Sciences, Oncology

Abstract

The MYCN gene plays 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. Herein, 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 AU-rich elements within the 3′-untranslated region (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 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 plays 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.