Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes

Prost, Sandrine; Bellamy, Christopher; Cunningham, Dean S.; Harrison, David J.

doi:10.1096/fasebj.12.2.181

Cited by 27 publications

(32 citation statements)

References 29 publications

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“…IRF-1 also cooperates with p53 to induce expression of the cdk inhibitor p21 WAF1 . 35,50 Although equivalent p53 expression levels were found between FancC Ϫ/Ϫ MEFs and FancC ϩ/ϩ MEFs and only minimal differences in p53 expression were found in human FA-C B lymphoblasts compared with normal cells, FA-C cells expressed significantly greater amounts of p21 WAF1 (Figure 1). There was no difference in p53 binding to its p21 WAF1 -binding site (data not shown), and expression of the IRF-1 independent cdk inhibitor p27 KIP1 was equivalent (Figure 1).…”

Section: Discussionmentioning

confidence: 97%

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Fagerlie

Diaz

Christianson

et al. 2001

Blood

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IntroductionFanconi anemia (FA) is an autosomal recessive disease characterized by progressive bone marrow failure, multiple congenital anomalies, and a high incidence of acute myelogenous leukemia. [1][2][3][4] Cells from FA patients are hypersensitive to the effects of DNA cross-linking agents, such as mitomycin C and diepoxybutane. 5,6 The disorder is genetically heterogeneous, with at least 7 different complementation groups. 7,8 The genes corresponding to group A (FANCA), C (FANCC), E (FANCE), F (FANCF), and G (FANCG) have been cloned. [9][10][11][12][13] Fanconi gene sequences show no significant homology to any known genes, and the functions of their gene products are unknown. 14,15 Hematopoietic precursor cells from children with FA of the C complementation group (FA-C) are excessively apoptotic and hypersensitive to a variety of cytokines known to induce apoptosis, including interferon ␥ (IFN␥). IFN␥ is a cytokine involved in host defense against viral infections and regulation of cell growth. 16 IFN␥ clearly plays a role in hematopoietic suppression and has been implicated in the pathogenesis of acquired aplastic anemia. [16][17][18][19][20][21][22] Cells with inactivating FANCC mutations are hypersensitive to the apoptotic effects of IFN␥, an effect that depends in part on an intact fas/fas-ligand pathway. [23][24][25][26] Specifically, exposure to low doses of IFN␥ in vitro primes a substantial fraction of FA-C progenitor cells to undergo apoptosis after subsequent exposure to fas ligand. Such doses of IFN␥ have no effect on normal hematopoietic progenitor cells. 23,24 Because of the influence of IFN␥ on the fas pathway, we sought to determine whether other IFN␥-inducible genes are hyperactive in FA-C cells. We carried out studies designed to analyze expression of IFN␥-inducible genes known to promote apoptosis and/or mitogenic inhibition in hematopoietic progenitor cells. We describe here studies revealing that the transactivators interferon regulatory factor-1 (IRF-1) and IFNstimulated gene factor 3 gamma subunit (ISGF3␥) and the cyclindependent kinase (cdk) inhibitor p21 WAF1 are expressed at constitutively higher levels in FA-C B lymphoblasts, low-density bone marrow cells (LDBMCs), and murine embryonic fibroblasts (MEFs), compared with cells expressing a normal FANCC. However, these proteins are expressed at normal levels in mature mutant fibroblasts, suggesting some degree of tissue or developmental stage specificity of FANCC function in control of these genes.IFN␥ exerts its effects, at least in part, through the Jak/signal transducer and activator of transcription (STAT) signaling pathway, 27,28 However, FA-C cells are defective in their ability to properly activate STAT1. 29 We show here that up-regulation of IFN␥-inducible genes occurs precisely in those cell types that fail to properly activate STAT1. For this reason, we hypothesized that loss of a STAT1-inducible transcriptional repressor may result in up-regulation of IFN␥-inducible genes in FA-C cells. Indeed, we found expression of the...

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Section: Discussionmentioning

confidence: 97%

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Fagerlie

Diaz

Christianson

et al. 2001

Blood

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“…More recently, it has been recognized that activation of IRF-1 leads to the expression of genes involved in a number of different cellular processes. In addition to the anti-viral response, these include: regulation of the cell cycle YuLee, 1992, 1994) and apoptosis (Kirchhoff and Hauser, 1999;Tamura et al, 1995); development of the T cell immune response (Matsuyama et al, 1993); susceptibility to transformation by oncogenes , and the response to genotoxic agents (Prost et al, 1998;Tanaka et al, 1996). Furthermore, deletion or point mutation of the IRF-1 gene (Eason et al, 1999;Willman et al, 1993), and exon skipping of IRF-1 mRNA have been linked to the development of human haemopoietic malignancies, such as leukaemia and myelodysplastic syndrome (Boultwood et al, 1993;Green et al, 1999;Willman et al, 1993), as well as, solid phase tumours of the gastro-intestinal tract Tamura et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Mouse embryonic fibroblasts (MEFs) and hepatocytes that are deficient in IRF-1 are compromised in their ability to undergo growth arrest (Tanaka et al, 1996) and to repair damaged DNA (Prost et al, 1998), respectively. Furthermore, maximal induction of the cyclin dependent kinase inhibitor, p21 (WAF1/CIP1), following exposure of MEFs to ionizing radiation (IR), appears to be dependent on both p53 and IRF-1 (Tanaka et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway

et al. 2002

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The mechanism by which genotoxic stress induces IRF-1 and the signalling components upstream of this antioncogenic transcription factor during the response to DNA damage are not known. We demonstrate that IRF-1 and the tumour suppressor protein p53 are coordinately up-regulated during the response to DNA damage in an ATM-dependent manner. Induction of IRF-1 protein by either ionizing radiation (IR) or etoposide occurs through a concerted mechanism involving increased IRF-1 expression/synthesis and an increase in the half-life of the IRF-1 protein. A striking defect in the induction of both IRF-1 mRNA and IRF-1 protein was observed in ATM deficient cells. Although ATM deficient cells failed to increase IRF-1 in response to genotoxic stress, the induction of IRF-1 in response to viral mimetics remained intact. Re-expression of the ATM kinase in AT cells restored the DNA damage inducibility of IRF-1, whilst the PI-3 kinase inhibitor wortmannin inhibited IRF-1 induction by DNA damage in ATM-positive cells. The data highlight a role for the ATM kinase in orchestrating the coordinated induction and transcriptional cooperation of IRF-1 and p53 to regulate p21 expression. Thus, IRF-1 is controlled by two distinct signalling pathways; a JAK/STAT-signalling pathway in viral infected cells and an ATM-signalling pathway in DNA damaged cells.

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“…Thus, although loss of IRF-1 by itself has no statistically significant effect on the rate of tumor formation, loss of IRF-1 in a p53-null background gives a dramatic increase in both tumor incidence and spectrum over that with loss of p53 alone, providing genetic evidence of interplay between these two factors. Mouse embryonic fibroblasts deficient in IRF-1 are compromised in their ability to undergo growth arrest in response to ionizing radiation (IR) (36), and IRF-1-null hepatocytes are impaired in their ability to repair damaged DNA (26). In addition, maximal induction of p21 (WAF1/CIP1) in IR-treated cells requires both IRF-1 and p53 (36).…”

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confidence: 99%

Interferon Regulatory Factor 1 Binding to p300 Stimulates DNA-Dependent Acetylation of p53

Dornan¹,

Eckert

Wallace

et al. 2004

Molecular and Cellular Biology

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Interferon regulatory factor 1 (IRF-1) and p53 control distinct sets of downstream genes; however, these two antioncogenic transcription factors converge to regulate p21 gene expression and to inhibit tumor formation. Here we investigate the mechanism by which IRF-1 and p53 synergize at the p21 promoter and show that stimulation of p21 transcription by IRF-1 does not require its DNA-binding activity but relies on the ability of IRF-1 to bind the coactivator p300 and to stimulate p53-dependent transcription by an allosteric mechanism. Deletion of the p300-binding sites in IRF-1 eliminates the ability of IRF-1 to stimulate p53 acetylation and associated p53 activity. Complementing this, small peptides derived from the IRF-1-p300 interface can bind to p300, stabilize the binding of p300 to DNA-bound p53, stimulate p53 acetylation in trans, and up-regulate p53-dependent activity from the p21 promoter. The nonacetylatable p53 mutant (p53-6KR) cannot be stimulated by IRF-1, further suggesting that p53 acetylation is the mechanism whereby IRF-1 modifies p53 activity. These data expand the core p300-p53 protein LXXLL and PXXP interface by including an IRF-1-p300 interface as an allosteric modifier of DNA-dependent acetylation of p53 at the p21 promoter.

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Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes

Cited by 27 publications

References 29 publications

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes

Regulation of the IRF-1 tumour modifier during the response to genotoxic stress involves an ATM-dependent signalling pathway

Interferon Regulatory Factor 1 Binding to p300 Stimulates DNA-Dependent Acetylation of p53

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