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(American Journal of Pathology. 2001;158:2067-2077.)
© 2001 American Society for Investigative Pathology

Regular Article

p53 Cellular Localization and Function in Neuroblastoma

Evidence for Defective G1 Arrest Despite WAF1 Induction in MYCN-Amplified Cells

Deborah A. Tweddle*{dagger}, Archie J. Malcolm{ddagger}, Michael Cole{dagger}§, Andrew D.J. Pearson{dagger} and John Lunec*

From the Cancer Research Unit,*
The Medical School, University of Newcastle, Newcastle-upon-Tyne; the Departments of Child Health{dagger}
and Pathology,{ddagger}
Royal Victoria Infirmary, Newcastle-upon-Tyne; and the Department of Statistics,§
University of Newcastle, Newcastle-upon-Tyne, United Kingdom

This study investigated the hypothesis that p53 accumulation in neuroblastoma, in the absence of mutation, is associated with functional inactivation, which interferes with downstream mediators of p53 function. To test this hypothesis, p53 expression, location, and functional integrity was examined in neuroblastoma by irradiating 6 neuroblastoma cell lines and studying the effects on p53 transcriptional function, cell cycle arrest, and induction of apoptosis, together with the transcriptional function of p53 after irradiation in three ex vivo primary, untreated neuroblastoma tumors. p53 sequencing showed five neuroblastoma cell lines, two of which were MYCN-amplified, and that all of the tumors were wild-type for p53. p53 was found to be predominantly nuclear before and after irradiation and to up-regulate the p53 responsive genes WAF1 and MDM2 in wild-type p53 cell lines and a poorly-differentiated neuroblastoma, but not a differentiating neuroblastoma or the ganglioneuroblastoma part of a nodular ganglioneuroblastoma in short term culture. This suggests intact p53 transcriptional activity in proliferating neuroblastoma. Irradiation of wild-type p53 neuroblastoma cell lines led to G1 cell cycle arrest in cell lines without MYCN amplification, but not in those with MYCN amplification, despite induction of WAF1. This suggests MYCN amplification may alter downstream mediators of p53 function in neuroblastoma.




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