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. 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.

Cooperative activity between HER oncogenes and the tumor suppressor IRF-1 results in apoptosis

“…Although BAX expression is not modulated during the combined activation of HER1 and IRF-1 (data not shown) the experiments demonstrate a further similarity between IRF-1 and p53. It has been reported earlier that both tumor suppressor proteins cooperate in response to DNA damage (Tamura et al, 1995;Tanaka et al, 1996).…”

“…The principle of synergistic action of transcription factors with IRF-1 is quite common; IRF-1 has been shown to cooperatively interact with TFIIB (Wang et al, 1996); NF-kB (Drew et al, 1995), and STAT1 (Chon et al, 1996). It is also described that IRF-1 together with p53 induces the cell cycle inhibitor p21 (Tanaka et al, 1996). However, so far we were not able to detect a direct interaction of IRF-1 with one of the STAT proteins, neither by gel retardation nor by a two hybrid system in mammalian cells (data not shown).…”

“…MHC class I (Hobart et al, 1996;Salkowski et al, 1996), iNOS (Kamijo et al, 1994) and GBP (Briken et al, 1995). IRF-1 is also necessary for proper expression of IL-15 (Ogasawara et al, 1998), p21 (Tanaka et al, 1996), and IFN-b (Fujita et al, 1993). Studies with IRF-1 knock-out cells demonstrate that IRF-1 is involved in the differentiation and function of NK cells (Ohteki et al, 1998;Ogasawara et al, 1998), in the generation of the TH 1 type of T helper cell and DNA damage (Tamura et al, 1997;Tanaka et al, 1996).…”

“…IRF-1 is also necessary for proper expression of IL-15 (Ogasawara et al, 1998), p21 (Tanaka et al, 1996), and IFN-b (Fujita et al, 1993). Studies with IRF-1 knock-out cells demonstrate that IRF-1 is involved in the differentiation and function of NK cells (Ohteki et al, 1998;Ogasawara et al, 1998), in the generation of the TH 1 type of T helper cell and DNA damage (Tamura et al, 1997;Tanaka et al, 1996). Moreover, IRF-1 shows tumor suppressor activity under certain conditions (Tanaka et al, 1994b(Tanaka et al, , 1996 and IRF-1 overexpression inhibits cell growth (Kirchho et al, 1993).…”

MyD genes in negative growth control

“…It was found that IRF7/7 MEFs are de®cient in their ability to undergo DNA-damageinduced cell-cycle arrest (Tanaka et al, 1996). Transcriptional activation of the cyclin dependent kinase inhibitor (CDKI) p21 gene in these cells by irradiation, was found to be dependent both on p53 and IRF-1.…”