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Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell
W E Mercer1, M T Shields, D Lin
1Department of Pathology, Temple University School of Medicine, Philadelphia, PA 19140.
Abstract:
The p53 gene is a frequent target of mutation in a wide variety of human cancers. Previously, it was reported that conditional expression of wild-type p53 protein in a cell line (GM47.23) derived from a human glioblastoma multiform tumor had a negative effect on cell proliferation. We have now investigated the effect that induction of wild-type p53 protein in this cell line has on the expression of the proliferating-cell nuclear antigen gene. The proliferating-cell nuclear antigen gene encodes a nuclear protein that is an auxiliary factor of DNA polymerase delta and part of the DNA replication machinery of the cell. We show that inhibition of cell cycle progression into S-phase after induction of wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen mRNA and protein expression.
Insights
Introducing wild-type p53 protein into glioblastoma cells inhibits proliferation by down-regulating proliferating-cell nuclear antigen (PCNA) gene expression, impacting DNA replication.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 gene is frequently mutated in human cancers.
- Wild-type p53 protein expression can inhibit glioblastoma cell proliferation.
Purpose of the Study:
- To investigate the effect of wild-type p53 induction on proliferating-cell nuclear antigen (PCNA) gene expression in a human glioblastoma cell line.
- To understand the molecular mechanisms underlying p53-mediated cell cycle arrest.
Main Methods:
- Conditional expression of wild-type p53 protein in GM47.23 glioblastoma cells.
- Analysis of PCNA mRNA and protein levels following p53 induction.
- Cell cycle progression analysis.
Main Results:
- Induction of wild-type p53 protein inhibited cell cycle progression into S-phase.
- PCNA mRNA and protein expression were selectively down-regulated.
- This suggests PCNA is a target gene suppressed by wild-type p53.
Conclusions:
- Wild-type p53 suppresses glioblastoma cell proliferation by down-regulating PCNA expression.
- This mechanism contributes to p53's role as a tumor suppressor.