Oncogenic Potential of a Dominant Negative Mutant of Interferon Regulatory Factor 3

Kim, Tae Young; Lee, Kyoung Hu; Chang, Seungwoo; Chung, Cheolho; Lee, Han Woong; Yim, Jeongbin; Kim, Tae Kook

doi:10.1074/jbc.m205792200

Cited by 43 publications

(28 citation statements)

References 34 publications

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“…Although IRF3 is part of a family of IFN regulatory transcription factors that contribute to cellular antiviral responses, mounting data suggest that IRF3 and its signaling pathway might have a potential for antioncogenic function. The expression of a dominant negative IRF3 mutant (IRF3D) that specifically inhibits expression of IRF3 target genes facilitated oncogenic transformation in vitro and in vivo (32). Prolyl isomerase Pin1, a potential oncogene (33), was shown to negatively regulate the IRF3-dependent innate antiviral response by stimulating proteasome-dependent degradation of IRF3 (34).…”

Section: Discussionmentioning

confidence: 99%

Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

Kim

Lee²,

Oh³

et al. 2007

Cancer Research

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IFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PMLpromoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference-mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression. [Cancer Res 2007; 67(23):11133-40]

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Section: Discussionmentioning

confidence: 99%

Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

Kim

Lee²,

Oh³

et al. 2007

Cancer Research

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“…Indeed, IRF-3 was shown to display direct tumor suppressor activity in vitro. [36][37][38][39] In vivo, this effect is also mediated through modulation of the immune response. 40 IL-12 plays an important role in the control of neoplastic transformation 2 and it was recently shown that IRF-1-mediated host defense against lymphoid malignancies was dependent on IL-12 production.…”

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation

Goriely

Molle

Nguyen

et al. 2006

Blood

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“…IRF6 is the least understood of the ninemember IRF family. Functions for this family of transcription factors have generally been associated with the induction and regulation of type I interferons and interferon-inducible genes following pathogenic insult but have also been linked to the cellular processes of growth control, apoptosis, tumor suppression, and embryonic development (12)(13)(14)(15)(16)(17)(21)(22)(23)(24)(25). Notably, recent studies indicate a crucial role for IRF6 in palatal development (26 -27).…”

Section: Discussionmentioning

confidence: 99%

Mammary Serine Protease Inhibitor (Maspin) Binds Directly to Interferon Regulatory Factor 6

Bailey

Khalkhali‐Ellis

Kondo

et al. 2005

Journal of Biological Chemistry

136

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Since its reported discovery in 1994, maspin (mammary serine protease inhibitor) has been characterized as a class II tumor suppressor by its ability to promote apoptosis and inhibit cell invasion. Maspin is highly expressed in normal mammary epithelial cells but reduced or absent in aggressive breast carcinomas. However, despite efforts to characterize the mechanism(s) by which maspin functions as a tumor suppressor, its molecular characterization has remained somewhat elusive. Therefore, in an attempt to identify maspin-interacting proteins and thereby gain insight into the functional pathways of maspin, we employed a maspin-baited yeast twohybrid system and subsequently identified Interferon Regulatory Factor 6 (IRF6) as a maspin-binding protein. IRF6 belongs to the IRF family of transcription factors, which is best known for its regulation of interferon and interferon-inducible genes following a pathogenic stimulus. Although many of the IRF family members have been well characterized, IRF6 remains poorly understood. We report that IRF6 is expressed in normal mammary epithelial cells and that it directly associates with maspin in a yeast two-hybrid system and in vitro. The interaction occurs via the conserved IRF protein association domain and is regulated by phosphorylation of IRF6. We have shown that, similar to maspin, IRF6 expression is inversely correlated with breast cancer invasiveness. We further demonstrated that the transient re-expression of IRF6 in breast cancer cells results in an increase of N-cadherin and a redistribution of vimentin commensurate with changes in cell morphology, suggestive of an epithelial-to-mesenchymal transition event. Concomitantly, we showed that maspin acts as a negative regulator of this process. These findings help to elucidate the molecular mechanisms of maspin and suggest an interactive role between maspin and IRF6 in regulating cellular phenotype, the loss of which can lead to neoplastic transformation. Maspin2 (mammary serine protease inhibitor, SerpinB5) was first isolated by subtractive hybridization and differential display as a protein that is expressed in normal mammary epithelial cells but reduced or absent in breast carcinomas (1). Since its initial discovery, maspin has been shown to inhibit tumor invasion and metastasis in breast cancer cells (2). Further studies implicate maspin as an angiogenesis inhibitor by its ability to block neovascularization and reduce tumor-associated microvessels and also demonstrate a role for maspin in the induction of apoptosis of tumor cells (3-4). In addition, the overexpression of maspin in transgenic mice disrupts normal mammary gland development by increasing apoptosis and disrupting cell differentiation (5). Despite the characterization of maspin as a tumor suppressor, the molecular mechanisms underlying maspin function are complex and remain predominantly unknown. Therefore, in an effort to decipher the molecular mechanisms of maspin, we employed a yeast two-hybrid system, in which we expressed full-length maspin as bai...

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Oncogenic Potential of a Dominant Negative Mutant of Interferon Regulatory Factor 3

Cited by 43 publications

References 34 publications

Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

Direct Transcriptional Activation of Promyelocytic Leukemia Protein by IFN Regulatory Factor 3 Induces the p53-Dependent Growth Inhibition of Cancer Cells

Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation

Mammary Serine Protease Inhibitor (Maspin) Binds Directly to Interferon Regulatory Factor 6

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