Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors.
- 9 May 1995
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 92 (10), 4407-4411
- https://doi.org/10.1073/pnas.92.10.4407
Abstract
Neuroblastoma (NB), a tumor arising from the sympathetic nervous system, is one of the most common malignancies in childhood. Several recent reports on the p53 genotype found virtually exclusive wild-type status in primary tumors, and it was postulated that p53 plays no role in the development of NB. Here, however, we report that the vast majority of undifferentiated NBs exhibit abnormal cytoplasmic sequestration of wild-type p53. This inability of p53 to translocate to the nucleus presumably prevents the protein from functioning as a suppressor. Thirty of 31 cases (96%) of undifferentiated NB showed elevated levels of wild-type p53 in the cytoplasm of all tumor cells concomittant with a lack of nuclear staining. p53 immunoprecipitation from tumor tissues showed a 4.5- to 8-fold increase over normal protein levels. All of 10 tumors analyzed harbored wild-type p53 by direct sequencing of full-length cDNA and Southern blot. In addition, no MDM-2 gene amplification was seen in all 11 tumors analyzed. In contrast, no p53 abnormality was detected in 14 differentiated ganglioneuroblastomas and 1 benign ganglioneuroma. We conclude that loss of p53 function seems to play a major role in the tumorigenesis of undifferentiated NB. This tumor might abrogate the transactivating function of p53 by inhibiting its access to the nucleus, rather than by gene mutation. Importantly, our results suggest that (i) this could be a general mechanism for p53 inactivation not limited to breast cancer (where we first described it) and that (ii) it is found in a tumor previously not thought to be affected by p53 alteration.Keywords
This publication has 29 references indexed in Scilit:
- A transcriptionally active DNA-binding site for human p53 protein complexes.Molecular and Cellular Biology, 1992
- Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas.1992
- Expression of p53 in human neuroblastoma- and neuroepithelioma-derived cell lines.1992
- p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts.Genes & Development, 1991
- Nuclear localization is essential for the activity of p53 protein.1991
- Involvement of wild-type p53 in pre-B-cell differentiation in vitro.Proceedings of the National Academy of Sciences, 1991
- The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53Cell, 1990
- International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma.Journal of Clinical Oncology, 1988
- MODULATION OF MR-53,000 PROTEIN WITH INDUCTION OF DIFFERENTIATION OF HUMAN NEURO-BLASTOMA CELLS1988
- Amplification of N- myc in Untreated Human Neuroblastomas Correlates with Advanced Disease StageScience, 1984