COOPERATION OF THE TUMOR SUPPRESSORS IRF-1 AND P53 IN RESPONSE TO DNA-DAMAGE

NORMALLY growing cells promptly cease DNA synthesis when exposed to ge notoxic stresses, such as radiation, and this cell-cycle arrest preven ts the accumulation of mutations(1,2). The transcription factor interf eron regulatory factor (IRF)-1 is essential for the regulation of the interferon system(3-5), inhibits cell growth, and manifests tumour-sup pressor activities(6,7). Here we show that mouse embryonic fibroblasts (EFs) lacking LRF-1 are deficient in their ability to undergo DNA-dam age-induced cell-cycle arrest. A similar phenotype has been observed i n EFs lacking the tumour suppressor p53 (refs 8, 9), although the expr ession of IRF-1 and p53 are independent of one another. Furthermore, w e show that transcriptional induction of the gene encoding p21 (WAF1, CIP1)(10-12), a cell-cycle inhibitor, by gamma-irradiation is dependen t on both p53 and IRF-1, and that the p21 promoter is activated, eithe r 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 co mmon target genes.