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

Hu, Guodong; Mancl, Margo E.; Barnes, Betsy J.

doi:10.1158/0008-5472.can-05-0583

Cited by 114 publications

(152 citation statements)

References 39 publications

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“…IRF5 is transcriptionally induced through the activation of p53, and indeed Irf5 Ϫ/Ϫ cells showed a similar phenotype to Trp53 Ϫ/Ϫ cells, indicating that IRF5 is essential to the apoptotic response. In contrast, unlike previous reports (17,19), our findings indicate that the induction of the p21 WAF1/Cip1 gene and the induction of cell cycle arrest normally occur in Irf5 Ϫ/Ϫ cells. Therefore, although IRF5 is one of the target genes of p53, it seems to be selectively involved in apoptosis but not in cell cycle arrest.…”

Section: Discussioncontrasting

confidence: 99%

“…The balance between cell cycle arrest and apoptosis is critical to the host's ability to eliminate cancerous cells, while saving the normal cells. IRF5 has been implicated in the induction of cell cycle arrest and apoptosis in response to genotoxic stresses (17)(18)(19). Indeed, IRF5 undergoes nuclear translocation upon DNA damage (ref.…”

Section: Role Of Irf5 In Cell Cycle Arrest and Apoptosis In Response Tomentioning

confidence: 99%

“…Several studies, employing overexpression or RNA interference assays using cultured cell lines, have suggested that IRF5 plays a role in inducing antiviral responses (16) as well as stress-induced cell cycle arrest and apoptosis (17)(18)(19); however, it remains to be determined in detail how these responses are affected in primary cells carrying a null mutation in the Irf5 alleles.…”

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confidence: 99%

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Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression

Yanai

Chen

Inuzuka

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

190

223

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Host defense consists of two main aspects, namely, immune response to invading pathogens and suppression of tumor development. A family of transcription factors, IFN regulatory factors (IRFs), has recently gained much attention in terms of its critical role in linking these two aspects of host defense, wherein IRF5 was previously shown to play a critical role in the induction of proinflammatory cytokines by activation of Toll-like receptors. In the present study, using IRF5 gene-targeted mice (Irf5 ؊/؊ mice), we demonstrate another facet of the IRF5 function in the regulation of immune response and tumor suppression. We show that IRF5 is critical for antiviral immunity by showing that Irf5 ؊/؊ mice are highly vulnerable to viral infections, accompanied by a decrease in type I IFN induction in the sera. Furthermore, we show that Irf5 ؊/؊ fibroblasts are resistant to apoptosis upon viral infection, resulting in an enhanced viral propagation. Finally, we provide evidence that IRF5 is critical for the induction of apoptosis, but not in cell cycle arrest, in response to DNA damage and that IRF5 functions as a tumor suppressor by acting on a pathway that may be distinct from that for p53. These results, together with the dual regulation of IRF5 gene expression by IFN signaling and p53, may provide a new link in the transcriptional network underlying antiviral immunity and tumor suppression.A n efficient and regulated cellular response is central to host defense, and it is coordinated by a genetic regulatory network in which a given transcription factor controls the expression of a set of diverse target genes depending on the cell type and/or the nature of cellular stimuli. Signaling in the immune system elicited by infection with viruses or bacteria usually leads to the production of type I IFN and inflammatory cytokines, resulting in the elimination of these pathogens (1, 2). Yet another important aspect of immune signal is the induction of apoptosis, which may be termed an altruistic suicide, which inhibits the further spread of infectious pathogens (3). This apoptotic response is highly similar to the response to genotoxic agents, such as ionizing radiation and certain anticancer drugs, which also induce cellular apoptosis, that is, one of the hallmarks of tumor suppression (4, 5). Indeed, recent studies have expanded the concept of a close relationship between the immune signaling system and oncogenesis (6, 7).IFN regulatory factor (IRF) family members have been implicated as critical transcription factors that sense various environmental stresses and induce various genes required for an adequate cellular response (8-12). The first family member to be characterized was IRF1, which plays a critical role in the induction of both antiviral immunity and apoptosis of cells exposed to DNA-damaging agents (13,14). Indeed, IRF1 cooperates with the tumor suppressor p53 to induce cell cycle arrest through the induction of p21 WAF1/Cip1 , and IRF1 induces apoptosis of cells expressing an oncogene. In addition, IRF8 (also kno...

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Section: Discussioncontrasting

confidence: 99%

Section: Role Of Irf5 In Cell Cycle Arrest and Apoptosis In Response Tomentioning

confidence: 99%

mentioning

confidence: 99%

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Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression

Yanai

Chen

Inuzuka

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

190

223

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“…Several studies have revealed that IRF5 plays an antitumor role through the induction of cell death programs by cellintrinsic and immune-mediated mechanisms (17)(18)(19). Our findings that IRF5 is selectively activated in CSC-R suggest that this transcription factor may potentially have unique functions distinct from those it has in chemosensitive tumors and immune cells.…”

Section: Csc-r-derived Irf5 Renders Myeloid Cells Competent To Promotmentioning

confidence: 68%

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

et al. 2014

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Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14 þ monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-Rspecific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5 þ CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors.Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumorassociated CSF1 receptor þ M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments. Cancer Res; 74(10); 2698-709. Ó2014 AACR.

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“…[17][18][19][20] IRF5 is a critical mediator of signals triggered by TLRs. [21][22][23] Its phosphorylation and nuclear translocation leads to the overexpression of many proinflammatory genes including cytokines, chemokines and type 1 IFN.…”

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confidence: 99%

Opposed independent effects and epistasis in the complex association of IRF5 to SLE

et al. 2007

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Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, Po10 À17) and protection (rs729302, Po10 À6 ). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5 0 side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.

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

Cited by 114 publications

References 39 publications

Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression

Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

Opposed independent effects and epistasis in the complex association of IRF5 to SLE

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