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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Expression of C-terminal deleted p53 isoforms in neuroblastoma
David Goldschneider1, Emilie Horvilleur, Louis-François Plassa
1Centre National de Recherche Scientifique, UMR 8126, Institut Gustave Roussy, 94805 Villejuif, France.
Abstract:
The tumor suppressor gene, p53, is rarely mutated in neuroblastomas (NB) at the time of diagnosis, but its dysfunction could result from a nonfunctional conformation or cytoplasmic sequestration of the wild-type p53 protein. However, p53 mutation, when it occurs, is found in NB tumors with drug resistance acquired over the course of chemotherapy. As yet, no study has been devoted to the function of the specific p53 mutants identified in NB cells. This study includes characterization and functional analysis of p53 expressed in eight cell lines: three wild-type cell lines and five cell lines harboring mutations. We identified two transcription-inactive p53 variants truncated in the C-terminus, one of which corresponded to the p53beta isoform recently identified in normal tissue by Bourdon et al. [J. C. Bourdon, K. Fernandes, F. Murray-Zmijewski, G. Liu, A. Diot, D. P. Xirodimas, M. K. Saville and D. P. Lane (2005) Genes Dev., 19, 2122-2137]. Our results show, for the first time, that the p53beta isoform is the only p53 species to be endogenously expressed in the human NB cell line SK-N-AS, suggesting that the C-terminus truncated p53 isoforms may play an important role in NB tumor development.
Insights
The tumor suppressor p53 is rarely mutated in neuroblastoma (NB) but can be dysfunctional. This study found truncated p53 isoforms, including p53beta, play a role in NB tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The tumor suppressor gene p53 is rarely mutated in neuroblastoma (NB) at diagnosis.
- p53 dysfunction in NB can arise from conformational changes or cytoplasmic sequestration.
- p53 mutations are associated with drug resistance in NB tumors post-chemotherapy.
Purpose of the Study:
- To characterize and functionally analyze p53 variants in NB cell lines.
- To investigate the role of specific p53 mutants found in NB cells.
- To explore the significance of C-terminus truncated p53 isoforms in NB.
Main Methods:
- Analysis of p53 expression in eight NB cell lines (three wild-type, five mutant).
- Characterization of p53 variants, focusing on C-terminus truncated forms.
- Functional analysis of identified p53 mutants.
Main Results:
- Identified two transcription-inactive p53 variants with C-terminal truncations.
- One identified variant corresponds to the p53beta isoform.
- The p53beta isoform was the sole endogenous p53 species in the SK-N-AS NB cell line.
Conclusions:
- C-terminus truncated p53 isoforms, including p53beta, may be crucial in neuroblastoma development.
- The p53beta isoform's role in NB warrants further investigation.
- Understanding p53 dysfunction mechanisms is key for NB treatment strategies.
