The Role of MYCN in the Failure of MYCN Amplified Neuroblastoma Cell Lines to G1 Arrest After DNA Damage

Emma Bell, Rakesh Premkumar, Jane Carr, Xiaohong Lu, Penny E Lovat, Ursula R Kees, John Lunec and Deborah Tweddle

volume 5 | issue 22

15 november 2006
Pages: 2639 - 2647

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We previously reported that 3 p53 wild type (wt) MYCN amplified (MNA) neuroblastoma cell lines failed to G1 arrest after DNA damage despite induction of p53, p21WAF1 and MDM2. We hypothesised that this was due to high MYCN expression. p53 responses to DNA damage were examined in an additional 13 p53 wt neuroblastoma cell lines. MNA was significantly associated with a failure to G1 arrest after DNA damage (p<0.001) and higher levels of apoptosis after irradiation (p<0.05). p21WAF1 and hypophosphorylated (hypo) RB accumulation post irradiation were significantly lower in cell lines that failed to G1 arrest (p<0.05). Conditional MYCN expression in non-MNA SHEP Tet21N cells did not affect the G1 arrest after irradiation. MYCN knockdown using siRNA in 3 p53 wt MNA cell lines did not restore a G1 arrest after irradiation, but increased the baseline G1 population, p21WAF1 and hypo RB expression. MYCN siRNA also caused a G1 arrest in a p53 mutant MNA cell line. This study is the first to determine that MNA correlates with a failure to G1 arrest and attenuated p21WAF1 induction; however MYCN expression alone is not causally responsible.