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p53 is nuclear and functional in both undifferentiated and differentiated neuroblastoma

Lookup NU author(s): Dr Lindi Chen, Professor Archibald Malcolm, Dr Katrina Wood, Mike Cole, Professor Andrew Pearson, Professor John LunecORCiD, Professor Deborah Tweddle

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Abstract

Aberrant cytoplasmic sequestration has been reported as an alternative mechanism of p53 inactivation to mutation in neuroblastoma. We hypothesized that p53 localization and function in neuroblastoma is related to differentiation status. Eighty-two untreated and 24 paired pre and post-chemotherapy neuroblastomas were studied by immunocytochemistry for p53, p21WAF1, BAX, Bcl2 and Ki67. Predominantly nuclear p53 was detected in undifferentiated neuroblastoma, and both nuclear and cytoplasmic p53 in differentiating neuroblastoma. The nuclear p53 labeling index (LI) correlated with the Ki67 LI (r = 0.51, p < 0.001), and weakly with p21WAF1 (r = 0.37), but not with BAX or Bcl2. There was a significant reduction in p53, p21WAF1 and Ki67 LI after chemotherapy (p < 0.01), an increase in BAX (p < 0.05), but no change in Bcl2. p53 localization and function were examined in two p53 wild-type undifferentiated and 9-cis retinoic acid differentiated neuroblastoma cell lines. Using immunocytochemistry, immunofluorescence and cell fractionation, p53 was found to be predominantly nuclear in both undifferentiated and differentiated cells. Following irradiation, there was upregulation of p53, p21WAF1 and MDM2, but less induced PARP and caspase 3 cleavage in differentiated cells, suggesting intact p53 transcriptional function, but resistance to apoptosis. p53 function in undifferentiated and differentiated cells was confirmed by upregulation of p21WAF1 and MDM2 following Nutlin-3 treatment. In conclusion, p53 is predominantly nuclear and functional in neuroblastoma regardless of differentiation status. ©2007 Landes Bioscience.

Publication metadata

Author(s): Chen L, Malcolm AJ, Wood K, Cole M, Variend S, Cullinane C, Pearson ADJ, Lunec J, Tweddle DA

Publication type: Article

Publication status: Published

Journal: Cell Cycle

Year: 2007

Volume: 6

Issue: 21

Pages: 2685-2696

Print publication date: 01/11/2007

Date deposited: 24/11/2010

ISSN (print): 1538-4101

ISSN (electronic): 1551-4005

Publisher: Landes Bioscience

URL: http://dx.doi.org/10.4161/cc.6.21.4853

DOI: 10.4161/cc.6.21.4853

PubMed id: 17912039

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