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PMID: 11395384 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

p53 cellular localization and function in neuroblastoma: evidence for defective G(1) arrest despite WAF1 induction in MYCN-amplified cells.

The American journal of pathology ·Vol. 158 ·No. 6 ·2001-06-00 ·Pages 2067-77

Tweddle DA, Malcolm AJ, Cole M, Pearson AD, Lunec J

Abstract

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 G(1) 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.

MeSH Terms
Apoptosis/radiation effects Cell Cycle/radiation effects Cell Nucleus/metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclins/biosynthesis DNA Mutational Analysis G1 Phase/radiation effects Gene Amplification Genes, myc Humans Immunohistochemistry Neuroblastoma/genetics,metabolism,pathology Nuclear Proteins Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-mdm2 Transcription Factors/genetics,physiology Tumor Cells, Cultured Tumor Suppressor Protein p53/genetics,immunology,physiology
Chemicals
CDKN1A protein, human Cyclin-Dependent Kinase Inhibitor p21 Cyclins Nuclear Proteins Proto-Oncogene Proteins Transcription Factors Tumor Suppressor Protein p53 MDM2 protein, human Proto-Oncogene Proteins c-mdm2
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tweddle D A
Cancer Research Unit, The Medical School, University of Newcastle, Newcastle-upon-Tyne, United Kingdom. d.a.tweedle@newcastle.ac.uk
Malcolm A J
Cole M
Pearson A D
Lunec J
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)64678-0
Email
d.a.tweedle@newcastle.ac.uk
Published
2001-06-00
Pages
2067-77
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1892004
Subset
IM
External Links
PubMed source DOI: 10.1016/S0002-9440(10)64678-0 PMC Full Text View journal details
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