MYCN-directed centrosome amplification requires MDM2-mediated suppression of p53 activity in neuroblastoma cells
- PMID: 17363562
- DOI: 10.1158/0008-5472.CAN-06-1661
MYCN-directed centrosome amplification requires MDM2-mediated suppression of p53 activity in neuroblastoma cells
Abstract
The MYC family oncogenes cause transformation and tumor progression by corrupting multiple cellular pathways, altering cell cycle progression, apoptosis, and genomic instability. Several recent studies show that MYCC (c-Myc) expression alters DNA repair mechanisms, cell cycle checkpoints, and karyotypic stability, and this is likely partially due to alterations in centrosome replication control. In neuroblastoma cell lines, MYCN (N-Myc) expression induces centrosome amplification in response to ionizing radiation. Centrosomes are cytoplasmic domains that critically regulate cytokinesis, and aberrations in their number or structure are linked to mitotic defects and karyotypic instability. Whereas centrosome replication is linked to p53 and Rb/E2F-mediated cell cycle progression, the mechanisms downstream of MYCN that generate centrosome amplification are incompletely characterized. We hypothesized that MDM2, a direct transcriptional target of MYCN with central inhibitory effects on p53, plays a role in MYC-mediated genomic instability by altering p53 responses to DNA damage, facilitating centrosome amplification. Herein we show that MYCN mediates centrosome amplification in a p53-dependent manner. Accordingly, inhibition of the p53-MDM2 interaction with Nutlin 3A (which activates p53) completely ablates the MYCN-dependent contribution to centrosome amplification after ionizing radiation. We further show that modulating MDM2 expression levels by overexpression or RNA interference-mediated posttranscriptional inhibition dramatically affects centrosome amplification in MYCN-induced cells, indicating that MDM2 is a necessary and sufficient mediator of MYCN-mediated centrosome amplification. Finally, we show a significant correlation between centrosome amplification and MYCN amplification in primary neuroblastoma tumors. These data support the hypothesis that elevated MDM2 levels contribute to MYCN-induced genomic instability through altered regulation of centrosome replication in neuroblastoma.
Similar articles
-
Suppression of centrosome amplification after DNA damage depends on p27 accumulation.Cancer Res. 2006 Apr 15;66(8):4020-9. doi: 10.1158/0008-5472.CAN-05-3250. Cancer Res. 2006. PMID: 16618721
-
MYCN sensitizes neuroblastoma to the MDM2-p53 antagonists Nutlin-3 and MI-63.Oncogene. 2012 Feb 9;31(6):752-63. doi: 10.1038/onc.2011.270. Epub 2011 Jul 4. Oncogene. 2012. PMID: 21725357 Free PMC article.
-
Mdm2 deficiency suppresses MYCN-Driven neuroblastoma tumorigenesis in vivo.Neoplasia. 2009 Aug;11(8):753-62. doi: 10.1593/neo.09466. Neoplasia. 2009. PMID: 19649205 Free PMC article.
-
MDM2 as MYCN transcriptional target: implications for neuroblastoma pathogenesis.Cancer Lett. 2005 Oct 18;228(1-2):21-7. doi: 10.1016/j.canlet.2005.01.050. Cancer Lett. 2005. PMID: 15927364 Review.
-
The MYCN oncoprotein as a drug development target.Cancer Lett. 2003 Jul 18;197(1-2):125-30. doi: 10.1016/s0304-3835(03)00096-x. Cancer Lett. 2003. PMID: 12880971 Review.
Cited by
-
The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2208904119. doi: 10.1073/pnas.2208904119. Epub 2022 Nov 29. Proc Natl Acad Sci U S A. 2022. PMID: 36445966 Free PMC article.
-
Filamin A increases aggressiveness of human neuroblastoma.Neurooncol Adv. 2022 Feb 28;4(1):vdac028. doi: 10.1093/noajnl/vdac028. eCollection 2022 Jan-Dec. Neurooncol Adv. 2022. PMID: 35441138 Free PMC article.
-
Long Noncoding RNA NHEG1 Drives β-Catenin Transactivation and Neuroblastoma Progression through Interacting with DDX5.Mol Ther. 2020 Mar 4;28(3):946-962. doi: 10.1016/j.ymthe.2019.12.013. Epub 2020 Jan 11. Mol Ther. 2020. PMID: 31982037 Free PMC article.
-
Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells.Mol Carcinog. 2012 May;51(5):363-78. doi: 10.1002/mc.20795. Epub 2011 May 6. Mol Carcinog. 2012. PMID: 21557332 Free PMC article.
-
p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance.Front Oncol. 2012 Nov 28;2:173. doi: 10.3389/fonc.2012.00173. eCollection 2012. Front Oncol. 2012. PMID: 23226679 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous