The Ews/Fli-1 fusion gene changes the status of p53 in neuroblastoma tumor cell lines
Cancer Research, ISSN: 0008-5472, Vol: 64, Issue: 20, Page: 7288-7295
2004
- 9Citations
- 16Captures
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Metrics Details
- Citations9
- Citation Indexes9
- CrossRef8
- Captures16
- Readers16
- 16
Article Description
One hallmark of Ewing's sarcoma/peripheral neuroectodermal tumors is the presence of the Ews/Fli-1 chimeric oncogene. Interestingly, infection of neuroblastoma tumor cell lines with Ews/Fli-1 switches the differentiation program of neuroblastomas to Ewing's sarcoma/peripheral neuroectodermal tumors. Here we examined the status of cytoplasmically sequestered wt-p53 in neuroblastomas after stable expression of Ews/Fli-1. Immunofluorescence revealed that in the neuroblastoma-Ews/Fli-1 infectant cell lines, p53 went from a punctate-pattern of cytoplasmic sequestration to increased nuclear localization. Western blot analysis revealed that PARC was down-regulated in one neuroblastoma cell line but not expressed in the second. Therefore, decreased PARC expression could not fully account for relieving p53 sequestration in the neuroblastoma tumor cells. Neuroblastoma-Ews/Fli-1 infectant cell lines showed marked increases in p53 protein expression without transcriptional up-regulation. Interestingly, p53 was primarily phosphorylated, without activation of its downstream target p21. Western blot analysis revealed that whereas MDM2 gene expression does not change, p14, a negative protein regulator of MDM2, increases. These observations suggest that the downstream p53 pathway may be inactivated as a result of abnormal p53. We also found that p53 has an extended half-life in the neuroblastoma-Ews/ Fli-1 infectants despite the retention of a wild-type sequence in neuroblastoma-Ews/ Fli-1 infectant cell lines. We then tested the p53 response pathway and observed that the neuroblastoma parent cells responded to genotoxic stress, whereas the neuroblastoma-Ews/Fli-1 infectants did not. These results suggest that Ews/Fli-1 can directly abrogate the p53 pathway to promote tumorigenesis. These studies also provide additional insight into the relationship among the p53 pathway proteins.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=5644271511&origin=inward; http://dx.doi.org/10.1158/0008-5472.can-04-1610; http://www.ncbi.nlm.nih.gov/pubmed/15492248; https://aacrjournals.org/cancerres/article/64/20/7288/511901/The-Ews-Fli-1-Fusion-Gene-Changes-the-Status-of; http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-04-1610; https://syndication.highwire.org/content/doi/10.1158/0008-5472.CAN-04-1610; https://dx.doi.org/10.1158/0008-5472.can-04-1610; https://cancerres.aacrjournals.org/content/64/20/7288
American Association for Cancer Research (AACR)
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