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Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage
N Tanaka1, M Ishihara, M S Lamphier
1Department of Immunology, Faculty of Medicine, University of Tokyo, Japan.
Abstract:
Normally growing cells promptly cease DNA synthesis when exposed to genotoxic stresses, such as radiation, and this cell-cycle arrest prevents the accumulation of mutations. The transcription factor interferon regulatory factor (IRF)-1 is essential for the regulation of the interferon system, inhibits cell growth, and manifests tumour-suppressor activities. Here we show that mouse embryonic fibroblasts (EFs) lacking IRF-1 are deficient in their ability to undergo DNA-damage-induced cell-cycle arrest. A similar phenotype has been observed in EFs lacking the tumour suppressor p53 (refs 8, 9), although the expression of IRF-1 and p53 are independent of one another. Furthermore, we show that transcriptional induction of the gene encoding p21 (WAF1, CIP1), a cell-cycle inhibitor, by gamma-irradiation is dependent on both p53 and IRF-1, and that the p21 promoter is activated, either directly or indirectly, by both in a transient cotransfection assay. These two tumour-suppressor transcription factors therefore converge functionally to regulate the cell cycle through the activation of a common target gene.
Insights
Interferon regulatory factor (IRF)-1 is crucial for cell-cycle arrest following DNA damage. This study reveals IRF-1 and p53 converge to activate the p21 gene, a key cell-cycle inhibitor.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cell-cycle arrest prevents mutations during genotoxic stress.
- Interferon regulatory factor (IRF)-1 is a transcription factor involved in tumor suppression.
- Tumor suppressor p53 plays a role in cell-cycle regulation.
Purpose of the Study:
- To investigate the role of IRF-1 in DNA-damage-induced cell-cycle arrest.
- To explore the relationship between IRF-1, p53, and the cell-cycle inhibitor p21.
Main Methods:
- Utilizing mouse embryonic fibroblasts (EFs) lacking IRF-1.
- Comparing cellular responses to genotoxic stress in wild-type and knockout EFs.
- Employing transient cotransfection assays to analyze p21 promoter activity.
Main Results:
- EFs lacking IRF-1 exhibit impaired DNA-damage-induced cell-cycle arrest.
- IRF-1 and p53 act independently but are both required for p21 induction.
- Both IRF-1 and p53 can activate the p21 promoter.
Conclusions:
- IRF-1 is essential for DNA-damage-induced cell-cycle arrest.
- IRF-1 and p53 functionally converge on the p21 gene to regulate the cell cycle.
- This convergence highlights a shared pathway for tumor suppression.