The Experts below are selected from a list of 9207 Experts worldwide ranked by ideXlab platform

Yoshiaki Ito - One of the best experts on this subject based on the ideXlab platform.

  • RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer Factor of the restriction-point
    2019
    Co-Authors: Jung-won Lee, Da-mi Kim, Ju-won Jang, Tae-geun Park, You-soub Lee, Xin-zi Chi, Il Yeong Park, Jin-won Hyun, Soo-hyun Song, Yoshiaki Ito
    Abstract:

    The Transcription Factor RUNX3 plays a key role in the restriction point of cell cycle. Here the authors showed that RUNX3 binds and opens chromatin structure of restriction point associated genes, by sequential recruitment of chromatin remodeling complex, Transcription complex and cell cycle regulators

  • RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α
    2012
    Co-Authors: Bo Huang, Yoshiaki Ito, Kosei Ito, Manuel Saltotellez, Chee Wee Ong, Y H Tsang, Gaoxi Xiao, David J Shapiro
    Abstract:

    Transcription Factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female RUNX3(+/-) mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen-dependent proliferation and transformation potential of ERα-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERα-dependent transactivation by reducing the stability of ERα. Consistent with its ability to regulate the levels of ERα, expression of RUNX3 inversely correlates with the expression of ERα in breast cancer cell lines, human breast cancer tissues and RUNX3(+/-) mouse mammary tumors. By destabilizing ERα, RUNX3 acts as a novel tumor suppressor in breast cancer.

  • RUNX3 functions as an oncogene in ovarian cancer
    2011
    Co-Authors: Cecilia Wei Lin Lee, Yoshiaki Ito, Manuel Saltotellez, Chee Wee Ong, Linda Shyue Huey Chuang, Shunichi Kimura, Soak Kuan Lai, Benedict Yan, Mahesh Choolani
    Abstract:

    Abstract Objective The Runt domain Transcription Factor, RUNX3, has been shown to be a tumor suppressor in a variety of cancers including gastric, colon and breast cancer. Interestingly, an oncogenic role for RUNX3 has also been suggested in basal cell carcinoma and head and neck cancer. Here, we explore the role of RUNX3 in ovarian cancer. Methods Expression of RUNX3 mRNA and protein was evaluated in human ovarian cancer cell lines. In addition, subcellular localization of RUNX3 was also examined in cell lines and ovarian cancer tissues. Effect of exogenous RUNX3 expression and knockdown on cell proliferation was investigated by proliferation assays and a soft agar assay. Results Expression of RUNX3 was detected in the nucleus of ovarian cancer cell lines and ovarian cancer tissues and was found to play a growth stimulatory role. RUNX3 knockdown resulted in a decrease in cell proliferation in liquid media as well as in soft agar. Despite the fact that exogenous expression of RUNX3 strongly inhibits cell growth in many cell types, RUNX3 promoted cell growth in ovarian cancer cell lines not expressing RUNX3. Conclusion RUNX3 is frequently expressed in the nuclei of ovarian cancer cell lines and plays an oncogenic role in ovarian cancer.

  • claudin 1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells
    2010
    Co-Authors: Ti Ling Chang, Kosei Ito, Manuel Saltotellez, Qiang Liu, Hiroshi Fukamachi, Khay Guan Yeoh, Yoshiaki Ito
    Abstract:

    Background & Aims The Transcription Factor RUNX3 is a gastric tumor suppressor. Tumorigenic RUNX3 −/− gastric epithelial cells attach weakly to each other, compared with nontumorigenic RUNX3 +/+ cells. We aimed to identify RUNX3 target genes that promote cell-cell contact to improve our understanding of RUNX3's role in suppressing gastric carcinogenesis. Methods We compared gene expression profiles of RUNX3 +/+ and RUNX3 −/− cells and observed down-regulation of genes associated with cell-cell adhesion in RUNX3 −/− cells. Reporter, mobility shift, and chromatin immunoprecipitation assays were used to examine the regulation of these genes by RUNX3. Tumorigenesis assays and immunohistological analyses of human gastric tumors were performed to confirm the role of the candidate genes in gastric tumor development. Results Mobility shift and chromatin immunoprecipitation assays revealed that the promoter activity of the gene that encodes the tight junction protein claudin-1 was up-regulated via the binding of RUNX3 to the RUNX consensus sites. The tumorigenicity of gastric epithelial cells from RUNX3 −/− mice was significantly reduced by restoration of claudin-1 expression, whereas knockdown of claudin-1 increased the tumorigenicity of human gastric cancer cells. Concomitant expression of RUNX3 and claudin-1 was observed in human normal gastric epithelium and cancers. Conclusions The tight junction protein claudin-1 has gastric tumor suppressive activity and is a direct Transcriptional target of RUNX3. Claudin-1 is down-regulated during the epithelial-mesenchymal transition; RUNX3 might therefore act as a tumor suppressor to antagonize the epithelial-mesenchymal transition.

  • the Transcription Factor RUNX3 represses the neurotrophin receptor trkb during lineage commitment of dorsal root ganglion neurons
    2007
    Co-Authors: Kenichi Inoue, Yoshiaki Ito, Kosei Ito, Motomi Osato, Bernett Lee, Sukchul Bae
    Abstract:

    RUNX3, a Runt domain Transcription Factor, determines neurotrophin receptor phenotype in dorsal root ganglion (DRG) neurons. Molecular mechanisms by which RUNX3 controls distinct neurotrophin receptors are largely unknown. Here, we show that RUNX3 abolished mRNA induction of TRKB expression, and concomitantly altered the neurotrophin response in a differentiating neuroblastoma cell line. In contrast, RUNX3 did not play a significant role in TRKC regulation even under the relevant BMP signaling pathway. We identified putative regulatory elements of Ntrk2/NTRK2 (a gene that codes for TrkB) using an unbiased computational approach. One of these elements was a highly conserved intronic sequence that contains a cluster of Runx binding sites. In a primary culture of DRG neurons, endogenous RUNX3 bound to the consensus cluster, which had repressor activity against the Ntrk2 promoter under the control of NT-3 signaling. Consistent with these findings, RUNX3-deficient embryos showed an increased number of trkB+ DRG neurons and failed to maintain trkC expression. Taken together, RUNX3 determines TrkC positive sensory neuron identities through the Transcriptional repression of TrkB when Trk-BTrkC double positive neurons differentiate into TrkC single positive neurons.

Hua Tang - One of the best experts on this subject based on the ideXlab platform.

  • interferon γ promotes double stranded rna induced tlr3 dependent apoptosis via upregulation of Transcription Factor RUNX3 in airway epithelial cells
    2016
    Co-Authors: Huachen Gan, Qin Hao, Steven Idell, Hua Tang
    Abstract:

    Viral respiratory tract infections are the most common illness in humans. Infection of the respiratory viruses results in accumulation of viral replicative double-stranded RNA (dsRNA), which is one of the important components of infecting viruses for the induction of lung epithelial cell apoptosis and innate immune response, including the production of interferon (IFN). In the present study, we have investigated the regulation of dsRNA-induced airway epithelial cell apoptosis by IFN. We found that Transcription Factor RUNX3 was strongly induced by type-II IFNγ, slightly by type-III IFNλ, but essentially not by type-I IFNα in airway epithelial cells. IFNγ-induced expression of RUNX3 was predominantly mediated by JAK-STAT1 pathway and partially by NF-κB pathway. Interestingly, RUNX3 can be synergistically induced by IFNγ with a synthetic analog of viral dsRNA polyinosinic-polycytidylic acid [poly(I:C)] or tumor necrosis Factor-α (TNFα) through both JAK-STAT1 and NF-κB pathways. We further found that dsRNA poly(I:C)-induced apoptosis of airway epithelial cells was mediated by dsRNA receptor toll-like receptor 3 (TLR3) and was markedly augmented by IFNγ through the enhanced expression of TLR3 and subsequent activation of both extrinsic and intrinsic apoptosis pathways. Last, we demonstrated that upregulation of RUNX3 by IFNγ promoted TLR3 expression, thus amplifying the dsRNA-induced apoptosis in airway epithelial cells. These novel findings indicate that IFNγ promotes dsRNA-induced TLR3-dependent apoptosis via upregulation of Transcription Factor RUNX3 in airway epithelial cells. Findings from our study may provide new insights into the regulation of airway epithelial cell apoptosis by IFNγ during viral respiratory tract infection.

  • Transcription Factor RUNX3 is induced by influenza a virus and double strand rna and mediates airway epithelial cell apoptosis
    2016
    Co-Authors: Huachen Gan, Qin Hao, Steven Idell, Hua Tang
    Abstract:

    Influenza A virus (IAV) targets airway epithelial cells and exploits the host cell machinery to replicate, causing respiratory illness in annual epidemics and pandemics of variable severity. The high rate of antigenic drift (viral mutation) and the putative antigenic shift (reassortant strains) have raised the need to find the host cell inducible Factors modulating IAV replication and its pathogenesis to develop more effective antiviral treatment. In this study, we found for the first time that Transcription Factor RUNX3, a developmental regulator and tumor suppressor, was induced by IAV H1N1 and H3N2, viral RNA, a synthetic analog of viral double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid, and type-II interferon-γ (IFNγ) in human airway epithelial cells. Whereas RUNX3 was essentially not induced by type-I IFNα and type-III IFNλ, we show that RUNX3 induction by IAV infection and viral RNA is mediated through the innate immune receptor MDA5 and the IκB kinase-β-NF-κB pathway. Moreover, we provide substantial evidence indicating that RUNX3 plays a crucial role in airway epithelial cell apoptosis induced by IAV infection and dsRNA through the activation of extrinsic and intrinsic apoptosis pathways. Thus, we have identified RUNX3 as an inducible and important Transcription Factor modulating IAV-induced host epithelial cell apoptosis.

Kosei Ito - One of the best experts on this subject based on the ideXlab platform.

  • RUNX3 protects gastric epithelial cells against epithelial mesenchymal transition induced cellular plasticity and tumorigenicity
    2012
    Co-Authors: Dominic Chihcheng Voon, Kosei Ito, Hiroshi Fukamachi, Huajing Wang, Jason Kin Wai Koo, Tu Anh Pham Nguyen, Yit Teng Hor, Yehshiu Chu, Shing Leng Chan, Jean Paul Thiery
    Abstract:

    The Transcription Factor RUNX3 functions as a tumor suppressor in the gastrointestinal epithelium, where its loss is an early event in carcinogenesis. While RUNX3 acts concurrently as a mediator of TGF-β signaling and an antagonist of Wnt, the cellular changes that follow its loss and their contribution to tumorigenicity are not fully understood. Here, we report that the loss of RUNX3 in gastric epithelial cells results in spontaneous epithelial-mesenchymal transition (EMT). This produces a tumorigenic stem cell-like subpopulation, which remarkably expresses the gastric stem cell marker Lgr5. This phenomenon is due to the compounding effects of the dysregulation of the TGF-β and Wnt pathways. Specifically, RUNX3−/−p53−/− gastric epithelial cells were unexpectedly sensitized for TGF-β-induced EMT, during which the resultant induction of Lgr5 was enhanced by an aberrantly activated Wnt pathway. These data demonstrate a protective role for RUNX3 in safeguarding gastric epithelial cells against aberrant growth Factor signaling and the resultant cellular plasticity and stemness. STEM Cells2012;30:2088–2099

  • RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α
    2012
    Co-Authors: Bo Huang, Yoshiaki Ito, Kosei Ito, Manuel Saltotellez, Chee Wee Ong, Y H Tsang, Gaoxi Xiao, David J Shapiro
    Abstract:

    Transcription Factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female RUNX3(+/-) mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen-dependent proliferation and transformation potential of ERα-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERα-dependent transactivation by reducing the stability of ERα. Consistent with its ability to regulate the levels of ERα, expression of RUNX3 inversely correlates with the expression of ERα in breast cancer cell lines, human breast cancer tissues and RUNX3(+/-) mouse mammary tumors. By destabilizing ERα, RUNX3 acts as a novel tumor suppressor in breast cancer.

  • RUNX3 is required for the differentiation of lung epithelial cells and suppression of lung cancer
    2010
    Co-Authors: Kyeongsook Lee, Ju-won Jang, You-soub Lee, Xin-zi Chi, Kosei Ito, Jong Min Lee, Senthilkumar Cinghu, Janghyun Kim, Yunmi Goh, Heejun Wee
    Abstract:

    Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related Transcription Factor RUNX3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. RUNX3-/- mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, RUNX3-/- bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. RUNX3-/- epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging RUNX3+/- mice ( approximately 18 months after birth) and invariably exhibit reduced levels of RUNX3. As K-ras mutations are very rare in these adenomas, RUNX3+/- mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that RUNX3 is essential for lung epithelial cell differentiation, and that downregulation of RUNX3 is causally linked to the preneoplastic stage of lung adenocarcinoma.

  • claudin 1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells
    2010
    Co-Authors: Ti Ling Chang, Kosei Ito, Manuel Saltotellez, Qiang Liu, Hiroshi Fukamachi, Khay Guan Yeoh, Yoshiaki Ito
    Abstract:

    Background & Aims The Transcription Factor RUNX3 is a gastric tumor suppressor. Tumorigenic RUNX3 −/− gastric epithelial cells attach weakly to each other, compared with nontumorigenic RUNX3 +/+ cells. We aimed to identify RUNX3 target genes that promote cell-cell contact to improve our understanding of RUNX3's role in suppressing gastric carcinogenesis. Methods We compared gene expression profiles of RUNX3 +/+ and RUNX3 −/− cells and observed down-regulation of genes associated with cell-cell adhesion in RUNX3 −/− cells. Reporter, mobility shift, and chromatin immunoprecipitation assays were used to examine the regulation of these genes by RUNX3. Tumorigenesis assays and immunohistological analyses of human gastric tumors were performed to confirm the role of the candidate genes in gastric tumor development. Results Mobility shift and chromatin immunoprecipitation assays revealed that the promoter activity of the gene that encodes the tight junction protein claudin-1 was up-regulated via the binding of RUNX3 to the RUNX consensus sites. The tumorigenicity of gastric epithelial cells from RUNX3 −/− mice was significantly reduced by restoration of claudin-1 expression, whereas knockdown of claudin-1 increased the tumorigenicity of human gastric cancer cells. Concomitant expression of RUNX3 and claudin-1 was observed in human normal gastric epithelium and cancers. Conclusions The tight junction protein claudin-1 has gastric tumor suppressive activity and is a direct Transcriptional target of RUNX3. Claudin-1 is down-regulated during the epithelial-mesenchymal transition; RUNX3 might therefore act as a tumor suppressor to antagonize the epithelial-mesenchymal transition.

  • the Transcription Factor RUNX3 represses the neurotrophin receptor trkb during lineage commitment of dorsal root ganglion neurons
    2007
    Co-Authors: Kenichi Inoue, Yoshiaki Ito, Kosei Ito, Motomi Osato, Bernett Lee, Sukchul Bae
    Abstract:

    RUNX3, a Runt domain Transcription Factor, determines neurotrophin receptor phenotype in dorsal root ganglion (DRG) neurons. Molecular mechanisms by which RUNX3 controls distinct neurotrophin receptors are largely unknown. Here, we show that RUNX3 abolished mRNA induction of TRKB expression, and concomitantly altered the neurotrophin response in a differentiating neuroblastoma cell line. In contrast, RUNX3 did not play a significant role in TRKC regulation even under the relevant BMP signaling pathway. We identified putative regulatory elements of Ntrk2/NTRK2 (a gene that codes for TrkB) using an unbiased computational approach. One of these elements was a highly conserved intronic sequence that contains a cluster of Runx binding sites. In a primary culture of DRG neurons, endogenous RUNX3 bound to the consensus cluster, which had repressor activity against the Ntrk2 promoter under the control of NT-3 signaling. Consistent with these findings, RUNX3-deficient embryos showed an increased number of trkB+ DRG neurons and failed to maintain trkC expression. Taken together, RUNX3 determines TrkC positive sensory neuron identities through the Transcriptional repression of TrkB when Trk-BTrkC double positive neurons differentiate into TrkC single positive neurons.

Yoram Groner - One of the best experts on this subject based on the ideXlab platform.

  • RUNX3 specifies lineage commitment of innate lymphoid cells
    2015
    Co-Authors: Takashi Ebihara, Ditsa Levanon, Yoram Groner, Christina Song, Stacy H Ryu, Beatrice Plougasteldouglas, Liping Yang, Michael D Bern, Thaddeus S Stappenbeck, Marco Colonna
    Abstract:

    Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses to external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 subsets, the Transcriptional control of commitment to each ILC lineage is incompletely understood. Here we report that the Transcription Factor RUNX3 was essential for the normal development of ILC1 and ILC3 cells but not of ILC2 cells. RUNX3 controlled the survival of ILC1 cells but not of ILC3 cells. RUNX3 was required for expression of the Transcription Factor RORγt and its downstream target, the Transcription Factor AHR, in ILC3 cells. The absence of RUNX3 in ILCs exacerbated infection with Citrobacter rodentium. Therefore, our data establish RUNX3 as a key Transcription Factor in the lineage-specific differentiation of ILC1 and ILC3 cells.

  • carcinogen induced skin tumor development requires leukocytic expression of the Transcription Factor RUNX3
    2014
    Co-Authors: Omri Bauer, Joseph Lotem, Shay Hantisteanu, Yoram Groner
    Abstract:

    Carcinogen-induced skin tumorigenesis depends heavily on pro-inflammatory tumor-promoting processes. Here we show that leukocytic RUNX3 expression is central to the two-stage DMBA/TPA-induced skin tumorigenesis. RUNX3-null mice were highly-resistant to this process and concomitant ablation of RUNX3 in dendritic and T cells fully recapitulated this resistance. Mechanistically, this resistance was associated with a shift in the skin cytokine milieu towards a tumor non-permissive microenvironment. Specifically, leukocytic RUNX3 loss substantially increased the anti-tumorigenic cytokine thymic stromal lymphopoietin (TSLP) and profoundly decreased two pro-tumorigenic cytokines, interlukin-17a and osteopontin. Therefore, inflammation-mediated tumor promotion requires leukocytic RUNX3 expression, as its loss creates a unique cytokine composition that polarizes the tumor microenvironment to a potent anti-tumorigenic state.

  • Transcription Factor RUNX3 regulates interleukin 15 dependent natural killer cell activation
    2014
    Co-Authors: Ditsa Levanon, Varda Negreanu, Joseph Lotem, Dena Leshkowitz, Karen R Bone, Ori Brenner, Yoram Groner
    Abstract:

    Natural killer cells belong to the family of innate lymphoid cells comprising the frontline defense against infected and transformed cells. Development and activation of natural killer cells is highly dependent on interleukin-15 signaling. However, very little is known about the Transcription program driving this process. The Transcription Factor RUNX3 is highly expressed in natural killer cells, but its function in these cells is largely unknown. We show that loss of RUNX3 impaired interleukin-15-dependent accumulation of mature natural killer cells in vivo and under culture conditions and pregnant RUNX3(-/-) mice completely lack the unique population of interleukin-15-dependent uterine natural killer cells. Combined chromatin immunoprecipitation sequencing and differential gene expression analysis of wild-type versus RUNX3-deficient in vivo activated splenic natural killer cells revealed that RUNX3 cooperates with ETS and T-box Transcription Factors to drive the interleukin-15-mediated Transcription program during activation of these cells. RUNX3 functions as a nuclear regulator during interleukin-15-dependent activation of natural killer cells by regulating the expression of genes involved in proliferation, maturation, and migration. Similar studies with additional Transcription Factors will allow the construction of a more detailed Transcriptional network that controls natural killer cell development and function.

  • RUNX3 mediated Transcriptional program in cytotoxic lymphocytes
    2013
    Co-Authors: Joseph Lotem, Varda Negreanu, Ditsa Levanon, Dena Leshkowitz, Gilgi Friedlander, Yoram Groner
    Abstract:

    The Transcription Factor RUNX3 is highly expressed in CD8+ T and NK cytotoxic lymphocytes and is required for their effective activation and proliferation but molecular insights into the Transcription program regulated by RUNX3 in these cells are still missing. Using RUNX3-ChIP-seq and transcriptome analysis of wild type vs. RUNX3-/- primary cells we have now identified RUNX3-regulated genes in the two cell types at both resting and IL-2-activated states. RUNX3-bound genomic regions in both cell types were distantly located relative to gene Transcription start sites and were enriched for RUNX and ETS motifs. Bound genomic regions significantly overlapped T-bet and p300-bound enhancer regions in RUNX3-expressing Th1 helper cells. Compared to resting cells, IL-2-activated CD8+ T and NK cells contain three times more RUNX3-regulated genes that are common to both cell types. Functional annotation of shared CD8+ T and NK RUNX3-regulated genes revealed enrichment for immune-associated terms including lymphocyte activation, proliferation, cytotoxicity, migration and cytokine production, highlighting the role of RUNX3 in CD8+ T and NK activated cells.

  • RUNX3 and t box proteins cooperate to establish the Transcriptional program of effector ctls
    2009
    Co-Authors: Fernando Cruzguilloty, Joseph Lotem, Ditsa Levanon, Yoram Groner, Matthew E Pipkin, Ivana M Djuretic, Mathias G Lichtenheld, Anjana Rao
    Abstract:

    Activation of naive CD8+ T cells with antigen induces their differentiation into effector cytolytic T lymphocytes (CTLs). CTLs lyse infected or aberrant target cells by exocytosis of lytic granules containing the pore-forming protein perforin and a family of proteases termed granzymes. We show that effector CTL differentiation occurs in two sequential phases in vitro, characterized by early induction of T-bet and late induction of Eomesodermin (Eomes), T-box Transcription Factors that regulate the early and late phases of interferon (IFN) γ expression, respectively. In addition, we demonstrate a critical role for the Transcription Factor RUNX3 in CTL differentiation. RUNX3 regulates Eomes expression as well as expression of three cardinal markers of the effector CTL program: IFN-γ, perforin, and granzyme B. Our data point to the existence of an elaborate Transcriptional network in which RUNX3 initially induces and then cooperates with T-box Transcription Factors to regulate gene Transcription in differentiating CTLs.

Huachen Gan - One of the best experts on this subject based on the ideXlab platform.

  • interferon γ promotes double stranded rna induced tlr3 dependent apoptosis via upregulation of Transcription Factor RUNX3 in airway epithelial cells
    2016
    Co-Authors: Huachen Gan, Qin Hao, Steven Idell, Hua Tang
    Abstract:

    Viral respiratory tract infections are the most common illness in humans. Infection of the respiratory viruses results in accumulation of viral replicative double-stranded RNA (dsRNA), which is one of the important components of infecting viruses for the induction of lung epithelial cell apoptosis and innate immune response, including the production of interferon (IFN). In the present study, we have investigated the regulation of dsRNA-induced airway epithelial cell apoptosis by IFN. We found that Transcription Factor RUNX3 was strongly induced by type-II IFNγ, slightly by type-III IFNλ, but essentially not by type-I IFNα in airway epithelial cells. IFNγ-induced expression of RUNX3 was predominantly mediated by JAK-STAT1 pathway and partially by NF-κB pathway. Interestingly, RUNX3 can be synergistically induced by IFNγ with a synthetic analog of viral dsRNA polyinosinic-polycytidylic acid [poly(I:C)] or tumor necrosis Factor-α (TNFα) through both JAK-STAT1 and NF-κB pathways. We further found that dsRNA poly(I:C)-induced apoptosis of airway epithelial cells was mediated by dsRNA receptor toll-like receptor 3 (TLR3) and was markedly augmented by IFNγ through the enhanced expression of TLR3 and subsequent activation of both extrinsic and intrinsic apoptosis pathways. Last, we demonstrated that upregulation of RUNX3 by IFNγ promoted TLR3 expression, thus amplifying the dsRNA-induced apoptosis in airway epithelial cells. These novel findings indicate that IFNγ promotes dsRNA-induced TLR3-dependent apoptosis via upregulation of Transcription Factor RUNX3 in airway epithelial cells. Findings from our study may provide new insights into the regulation of airway epithelial cell apoptosis by IFNγ during viral respiratory tract infection.

  • Transcription Factor RUNX3 is induced by influenza a virus and double strand rna and mediates airway epithelial cell apoptosis
    2016
    Co-Authors: Huachen Gan, Qin Hao, Steven Idell, Hua Tang
    Abstract:

    Influenza A virus (IAV) targets airway epithelial cells and exploits the host cell machinery to replicate, causing respiratory illness in annual epidemics and pandemics of variable severity. The high rate of antigenic drift (viral mutation) and the putative antigenic shift (reassortant strains) have raised the need to find the host cell inducible Factors modulating IAV replication and its pathogenesis to develop more effective antiviral treatment. In this study, we found for the first time that Transcription Factor RUNX3, a developmental regulator and tumor suppressor, was induced by IAV H1N1 and H3N2, viral RNA, a synthetic analog of viral double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid, and type-II interferon-γ (IFNγ) in human airway epithelial cells. Whereas RUNX3 was essentially not induced by type-I IFNα and type-III IFNλ, we show that RUNX3 induction by IAV infection and viral RNA is mediated through the innate immune receptor MDA5 and the IκB kinase-β-NF-κB pathway. Moreover, we provide substantial evidence indicating that RUNX3 plays a crucial role in airway epithelial cell apoptosis induced by IAV infection and dsRNA through the activation of extrinsic and intrinsic apoptosis pathways. Thus, we have identified RUNX3 as an inducible and important Transcription Factor modulating IAV-induced host epithelial cell apoptosis.