title: MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells.
abstract: 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.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Gu
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: He
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: M
authors.initials: M
authors.lastname: Zhou
mesh_terms: D020413:3' Untranslated Regions; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2