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Gene regulation by temperature-sensitive p53 mutants: identification of p53 response genes
L Buckbinder1, R Talbott, B R Seizinger
1Department of Molecular Genetics and Cell Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08540.
Abstract:
The ability of the p53 protein to act as a sequence-specific transcriptional activator suggests that genes induced by p53 may encode critical mediators of p53 tumor suppression. Using a tetracycline-regulated p53 expression system and cDNA library subtraction procedure, we identified several p53-induced gene transcripts in human Saos-2 osteosarcoma cells that are novel on the basis of their size, regulation, and low abundance. Wild-type p53-dependent induction of these transcripts was observed in cells that are growth arrested by p53, as well as in cells that undergo apoptosis upon expression of an inducible wild-type p53 transgene. These results show that p53 activates the expression of numerous response genes and suggest that multiple effectors may play a role in mediating cellular functions of p53.
Insights
The p53 protein activates numerous genes, some novel, that mediate its tumor suppressor functions. These p53-induced genes are involved in cell cycle arrest and apoptosis, crucial for cancer suppression.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The p53 protein is a critical tumor suppressor.
- p53 functions as a sequence-specific transcriptional activator.
- Understanding p53-induced genes is key to elucidating its tumor suppression mechanisms.
Purpose of the Study:
- To identify novel genes regulated by wild-type p53.
- To investigate the role of p53-induced genes in cellular functions like growth arrest and apoptosis.
Main Methods:
- Utilized a tetracycline-regulated p53 expression system.
- Employed cDNA library subtraction to identify p53-induced transcripts.
- Analyzed gene induction in Saos-2 osteosarcoma cells.
Main Results:
- Identified several novel p53-induced gene transcripts.
- Confirmed wild-type p53-dependent induction of these transcripts.
- Observed transcript induction in both p53-mediated growth arrest and apoptosis.
Conclusions:
- p53 activates the expression of multiple response genes.
- Novel genes identified play roles in mediating p53's cellular functions.
- Multiple effectors likely contribute to p53's tumor suppressor activity.