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p53 isoform profiling in glioblastoma and injured brain
R Takahashi1, C Giannini, J N Sarkaria
1Mayo Clinic, Rochester, MN, USA.
Abstract:
The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10 to 70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, some of which can modulate full-length p53 activity in cancer. In this study, we characterized p53 isoform expression patterns in glioblastoma, gliosis, non-tumor brain and neural progenitor cells by SDS-PAGE, immunoblot, mass spectrometry and reverse transcription-PCR. We found that the most consistently expressed isoform in glioblastoma, Δ40p53, was uniquely expressed in regenerative processes, such as those involving neural progenitor cells and gliosis compared with tumor samples. Isoform profiling of glioblastoma tissues revealed the presence of both Δ40p53 and full-length p53, neither of which were detected in non-tumor cerebral cortex. Upon xenograft propagation of tumors, p53 levels increased. The variability of overall p53 expression and relative levels of isoforms suggest fluctuations in subpopulations of cells with greater or lesser capacity for proliferation, which can change as the tumor evolves under different growth conditions.
Insights
The tumor suppressor p53 gene has many forms (isoforms) that affect cancer. In glioblastoma, a specific p53 isoform, Δ40p53, is found in regenerative brain cells, not healthy brain tissue.
Area of Science:
- Molecular Biology
- Oncology
- Neuroscience
Background:
- The p53 gene is frequently mutated in human cancers, but mutation frequency varies widely.
- Mechanisms beyond direct mutation, such as p53 isoforms, can influence p53 activity in cancer.
- The p53 gene produces 12 isoforms that can modulate the activity of full-length p53.
Purpose of the Study:
- To characterize p53 isoform expression patterns in glioblastoma.
- To compare p53 isoform expression in glioblastoma with gliosis, non-tumor brain, and neural progenitor cells.
- To investigate the role of p53 isoforms in glioblastoma development and evolution.
Main Methods:
- Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
- Immunoblotting
- Mass spectrometry
- Reverse transcription-polymerase chain reaction (RT-PCR)
Main Results:
- The Δ40p53 isoform was consistently expressed in glioblastoma and uniquely found in regenerative processes (neural progenitor cells, gliosis).
- Glioblastoma tissues expressed both Δ40p53 and full-length p53, which were absent in non-tumor cerebral cortex.
- p53 levels increased upon xenograft propagation of glioblastoma tumors.
Conclusions:
- p53 isoform expression patterns differ between glioblastoma and normal brain tissues.
- The presence of Δ40p53 in regenerative cells suggests a role in cellular repair or proliferation.
- Variations in p53 isoforms may reflect dynamic changes in tumor cell subpopulations and their proliferative capacities during tumor evolution.
