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Outcome of the p53-mediated DNA damage response in neuroblastoma is determined by morphological subtype and MYCN expression

Lookup NU author(s): Dr Jane Carr-Wilkinson, Bojidar Goranov, Dr Chris RedfernORCiD, Dr Laura GambleORCiD, Professor John LunecORCiD, Professor Deborah Tweddle

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Abstract

Background: MYCN oncogene amplification occurs in 20-25% of neuroblastomas and is associated with a poor prognosis. We previously reported that MYCN amplified (MNA) p53 wild-type neuroblastoma cell lines failed to G 1 arrest in response to irradiation, but this could not be attributed to MYCN alone. Hypothesis: Genes co-amplified with MYCN and/or the predominant cell type, neuronal (N) or substrate adherent (S) phenotypes determine the downstream response to DNA damage in neuroblastoma cell lines. Results: No genes with a potential role in cell cycle regulation were consistently co-amplified in the MNA cell lines studied. High MYCN expressing NBLW-N cells failed to G 1 arrest following irradiation and showed impaired induction of p21 and MDM2, whereas low MYCN expressing NBLW-S cells underwent a G 1 arrest with induction of p21 and MDM2. Conversely N type cells underwent higher levels of apoptosis than S type cells. Following p53 knockdown in SHSY5Y N-type cells there was a decrease in apoptosis. Methods: The MYCN amplicons of five MNA and two non-MNA cell line were mapped using 50K Single Nucleotide Polymorphism (SNP) arrays. One MNA (NBL-W) and one non-MNA neuroblastoma cell line (SKNSH) were sub-cloned into N and S-type cells and the p53 pathway investigated after irradiation induced DNA damage. To determine the role of p53 it was knocked down using siRNA. Conclusions: The downstream response to DNA damage in p53 wild-type neuroblastoma cell lines is p53-dependent, and determined both by the morphological subtype and MYCN expression.

Publication metadata

Author(s): Carr-Wilkinson J, Griffiths R, Elston R, Goranov B, Redfern CPF, Gamble LD, Lunec J, Tweddle DA

Publication type: Article

Publication status: Published

Journal: Cell Cycle

Year: 2011

Volume: 10

Issue: 21

Pages: 3778-3787

Print publication date: 01/11/2011

ISSN (print): 1538-4101

ISSN (electronic): 1551-4005

Publisher: Landes Bioscience

URL: http://dx.doi.org/10.4161/cc.10.21.17973

DOI: 10.4161/cc.10.21.17973

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