Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage

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^1,2. The transcription factor interferon regulatory factor (IRF)-1 is essential for the regulation of the interferon system^3–5, inhibits cell growth, and manifests tumour-suppressor activities^6,7. 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)^10–12 a cell-cycle inhibitor, by γ-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 genes.