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

Pamment, Jessica; Ramsay, Eleanor; Kelleher, Michael O.; Dornan, David; Ball, Kathryn L.

doi:10.1038/sj.onc.1205981

Cited by 81 publications

(63 citation statements)

References 60 publications

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“…The onset of IRF1 protein induction by 24-h BrdU þ DMA treatment correlated with the induction of IFNb expression (Figure 2b), indicating that IRF1 occurs in early phases of interferon gene induction and, together with IRF7, can participate in the persistent activity of the IFN-JAK/STAT pathway in cells undergoing BDIS. In addition, we found elevated IRF1 in HeLa cells brought to senescence using camptothecin, etoposide (see also Pamment et al, 2002), doxorubicin, APH and HU (data not shown). Overall, the upregulation of transcripts of several ISGs indicated that BrdU þ DMA-induced activity of interferon-JAK/STAT signaling results in corresponding gene expression.…”

Section: Activation Of Ifn Pathway In Genotoxic Stressmentioning

confidence: 72%

Cytokine expression and signaling in drug-induced cellular senescence

et al. 2009

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Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2 0 -deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon c (IFNc), IFNb and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/ chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNb-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.

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Section: Activation Of Ifn Pathway In Genotoxic Stressmentioning

confidence: 72%

Cytokine expression and signaling in drug-induced cellular senescence

et al. 2009

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“…IRF-1 is thought to undergo posttranslational modification to activate IFN-stimulated genes (33), and IFN-g-induced tyrosine phosphorylation of IRF-1 leads to activation (34). Recently, it was shown that IRF-1 expression (mRNA and protein) and protein stability were controlled by an ATM signaling pathway in response to irradiation (9). Whereas IRF-5 is phosphorylated and activated by viral infection (21,22) or by stimulation with the toll-like receptor-7/8 inducer resiquimod (R-848; ref.…”

Section: Resultsmentioning

confidence: 99%

“…With regard to tumor suppressor activity, IRF-1, in particular, has received much attention over the past 10 years. Regulation of IRF-1 is thought to be controlled by two distinct signaling pathways; a Janusactivated kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway in virus-infected or IFNtreated cells and an ataxia telangiectasia mutated (ATM) signaling pathway in DNA-damaged cells (9). Genes downstream of IRF-1 in these two pathways include IFNB (10, 11), RNA-dependent protein kinase (12, 13), 2-5A synthetase (14,15), cyclin-dependent kinase inhibitor p21 (WAF1/CIP1; refs.…”

Section: Introductionmentioning

confidence: 99%

Signaling through IFN Regulatory Factor-5 Sensitizes p53-Deficient Tumors to DNA Damage–Induced Apoptosis and Cell Death

2005

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Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage-induced apoptosis. The combination IFN-B and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damageinduced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage-induced IRF-5 activation. Thus, IRF-5-regulated pathways may serve as a target for cancer therapeutics. (Cancer Res 2005; 65(16): 7403-12)

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“…30 Since overexpression of IRF1 leads to elevated PML transcripts, 80 increased levels of IRF1 found after drug treatment 35 may contribute to JAK/STAT-dependent PML expression in our present study. Moreover, ATM-dependent stabilization of IRF1 was reported after etoposide treatment, 81 and precise characterization sensitivity of BrdU-treated cells to light-induced DNA damage, cells were exposed to light only for minimal time periods necessary for handling. Senescence associated-β-galactosidase assay was performed as described 86 with modifications described in.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling

Hubáčková¹,

Nováková²,

Krejčíková³

et al. 2010

Cell Cycle

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the promyelocytic leukemia protein (pML) tumor suppressor is upregulated in several forms of cellular senescence, however the mechanism of its induction is elusive. Here we show that genotoxic drugs that induce senescence, such as 5-bromo-2'deoxyuridine (BrdU), thymidine (tMD), distamycin A (DMA), aphidicolin (ApH), etoposide (et) and camptothecin (Cpt) all evoke expansion of pML nuclear compartment and its association with persistent DNA lesions in several human cancer cell lines and normal diploid fibroblasts. this phenomenon was accompanied by elevation of pML transcripts after treatment with BrdU, tMD, DMA and Cpt. Chemical inhibition of all JAK kinases and RNAi-mediated knock-down of JAK1 suppressed pML expression, implicating JAK/StAt-mediated signaling in regulation of the pML gene. As pML protein stability remained unchanged after drug treatment, decreased protein turnover was unlikely to explain the senescence-associated increased abundance of pML. Furthermore, binding activity of Interferon Stimulated Response element (ISRe) within the pML gene promoter, and suppression of reporter gene activity after deletion of ISRe from the pML promoter region suggested that drug-induced pML transcription is controlled via transcription factors interacting with this element. Collectively, our data show that upregulation of the pML tumor suppressor in cellular senescence triggered by diverse drugs including clinically used anti-cancer chemotherapeutics relies on stimulation of pML transcription by JAK/StAt-mediated signaling, possibly evoked by the autocrine/paracrine activities of senescenceassociated cytokines.

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

Cited by 81 publications

References 60 publications

Cytokine expression and signaling in drug-induced cellular senescence

Cytokine expression and signaling in drug-induced cellular senescence

Signaling through IFN Regulatory Factor-5 Sensitizes p53-Deficient Tumors to DNA Damage–Induced Apoptosis and Cell Death

Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling

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