記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Autophagy is a. dynamic recycling system using lysosomal proteolysis that produces new proteins and energy for cellular renovation and homeostasis. Although macroautophagy is known to serve as a survival pathway in many cancer cells, the role of chaperone-mediated autophagy (CMA), a selective protein degradation system, in cancer is not fully understood. Here, we demonstrated that lysosomal proteolysis, but not macroautophagy, attenuated apoptosis induced by the tyrosine kinase inhibitor, crizotinib, in the non-small-cell lung cancer (NSCLC) cell line, EBC1. In EBC1 cells, crizotinib induced BIM-dependent apoptosis, which was enhanced by inhibition of lysosomal proteolysis. Moreover, degradation of the pro-survival protein, MCL1, by the ubiquitin-proteasome system was induced by inhibition of lysosomal proteolysis, and by inhibition of the expression of the CMA mediators, HSC70 (heat shock cognate protein 70 kDa) and LAMP2A (lysosome membrane protein type 2A), suggesting the existence of a CMAmediated MCL1 stabilization system in cancer cells. Indeed, the same MCL1 stabilization system was also observed in several NSCLC cell lines; in these cells, their specific molecular-targeted drug or ABT-263 (Navitoclax), the specific inhibitor of BCL-2 and BCL-X-L, but not of MCL1, effectively induced apoptosis in combination with CMA inhibition. Therefore, our results indicate a novel mechanism of MCL1 stabilization in lung cancers by CMA, and a candidate efficient combination chemotherapy method against lung cancers. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2016.12.037

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IMPACT JOURNALS LLC  

Noxa, a BH3-only pro-apoptotic BCL-2 family protein, causes apoptosis by specifically interacting with the anti-apoptotic protein MCL-1 to induce its proteasome-mediated degradation. We show here that the DNA damaging agents cisplatin and etoposide upregulate Noxa expression, which is required for the phosphorylation of MCL-1 at Ser64/Thr70 sites, proteasome-dependent degradation, and apoptosis. Noxa-induced MCL-1 phosphorylation at these sites occurs at the mitochondria and is primarily regulated by CDK2. MCL-1 and CDK2 form a stable complex and Noxa binds to this complex to facilitate the phosphorylation of MCL-1. When Ser64 and Thr70 of MCL-1 are substituted with alanine, the mutated MCL-1 is neither phosphorylated nor ubiquitinated, and becomes more stable than the wild-type protein. As a consequence, this mutant can inhibit apoptosis induced by Noxa overexpression or cisplatin treatment. These results indicate that Noxa-mediated MCL-1 phosphorylation followed by MCL-1 degradation is critical for apoptosis induced by DNA damaging agents through regulation of the Noxa/MCL-1/CDK2 complex.

DOI： 10.18632/oncotarget.9217

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Cisplatin is a highly effective anticancer drug for treatment of various tumors including non-small-cell lung cancer (NSCLC), and is especially useful in cases nonresponsive to molecular-targeted drugs. Accumulating evidence has shown that cisplatin activates the p53-dependent apoptotic pathway, but it also induces apoptosis in p53-mutated cancer cells. Here we demonstrated that DNA-damage inducible proapoptotic BH3 (Bcl-2 homology region 3)-only Bcl-2 family members, Noxa, Puma, Bim and Bid, are not involved in cisplatin-induced apoptosis in human NSCLC cell lines. In contrast, the expression of proapoptotic multidomain Bcl-2-family members, Bak and Bax, was induced by cisplatin in p53 dependent and-independent manners, respectively. Moreover, in wild-type p53-expressing cells, cisplatin mainly used the Bak-dependent apoptotic pathway, but this apoptotic pathway shifted to the Bax-dependent pathway by loss-of-function of p53. Furthermore, both Bak- and Bax-induced apoptosis was enhanced by the antiapoptotic Bcl-2 family member, Bcl-X-L knockdown, but not by Mcl-1 knockdown. From this result, we tested the effect of ABT-263 (Navitoclax), the specific inhibitor of Bcl-2 and Bcl-XL, but not Mcl-1, and found that ABT-263 synergistically enhanced cisplatin-induced apoptosis in NSCLC cells in the presence or absence of p53. These results indicate a novel regulatory system in cisplatin-induced NSCLC cell apoptosis, and a candidate efficient combination chemotherapy method against lung cancers. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2016.03.053

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記述言語：英語   出版者・発行元：HINDAWI LTD  

Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.

DOI： 10.1155/2016/7969286

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tumor suppressor p53 prevents tumorigenesis and tumor growth by suppressing the activation of several transcription factors, including nuclear factor-κB (NF-κB) and STAT3. On the other hand, p53 stimulates actin cytoskeleton remodeling and integrin-related signaling cascades. Here, we examined the p53-mediated link between regulation of the actin cytoskeleton and activation of NF-κB and STAT3 in MCF-7 cells and mouse embryonic fibroblasts (MEFs). In the absence of p53, STAT3 was constitutively activated. This activation was attenuated by depleting the expression of p65, a component of NF-κB. Integrin β3 expression and lamellipodia formation were also downregulated by NF-κB depletion. Inhibition of integrin αvβ3, Rac1 or Arp2/3, which diminished lamellipodia formation, suppressed STAT3 activation induced by p53 depletion. These results suggest that loss of p53 leads to STAT3 activation via NF-κB-dependent lamellipodia formation. Our study proposes a novel role for p53 in modulating the actin cytoskeleton through suppression of NF-κB, which restricts STAT3 activation. J. Cell. Physiol. 229: 696-704, 2014. © 2013 Wiley Periodicals, Inc.

DOI： 10.1002/jcp.24505

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

Oncogenic Ras induces cell transformation and promotes an invasive phenotype. The tumor suppressor p53 has a suppressive role in Ras-driven invasion. However, its mechanism remains poorly understood. Here we show that p53 induces activation of the mitochondrial protease high-temperature requirement A2 (HtrA2; also known as Omi) and prevents Ras-driven invasion by modulating the actin cytoskeleton. Oncogenic Ras increases accumulation of p53 in the cytoplasm, which promotes the translocation of p38 mitogen-activated protein kinase (MAPK) into mitochondria and induces phosphorylation of HtrA2/Omi. Concurrently, oncogenic Ras also induces mitochondrial fragmentation, irrespective of p53 expression, causing the release of HtrA2/Omi from mitochondria into the cytosol. Phosphorylated HtrA2/Omi therefore cleaves beta-actin and decreases the amount of filamentous actin (F-actin) in the cytosol. This ultimately down-regulates p130 Crk-associated substrate (p130Cas)-mediated lamellipodia formation, countering the invasive phenotype initiated by oncogenic Ras. Our novel findings provide insights into the mechanism by which p53 prevents the malignant progression of transformed cells.

DOI： 10.1083/jcb.201309107

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

The sensitivity to ABT-737, a prototype BH3 mimetic drug, varies in a broad range in small cell lung cancer (SCLC) cells. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is the critical determinant of ABT-737 sensitivity. We show here that Noxa regulates the localization and stability of MCL-1, an anti-apoptotic member, which results in modulating ABT-737 sensitivity. Mutations in Noxa within the BH3 domain, the carboxyl terminus mitochondrial targeting domain, or of ubiquitinated lysines not only change the localization and stability of Noxa itself but also affect the mitochondrial localization and phosphorylation/ubiquitination status of MCL-1 and consequently modulate sensitivity to ABT-737. Results of studies utilizing these mutant proteins indicate that Noxa recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation. The precise regulatory mechanisms of Noxa/MCL-1 expression and stability could provide alternative targets to modulate apoptosis induced by BH3 mimetic drugs or other chemotherapeutic reagents.

DOI： 10.1038/cddis.2014.6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Tumor suppressor p53 induces apoptosis by transcriptional induction of Noxa and Puma, which encode the proapoptotic BH3-only member of the Bcl-2 family proteins. In the p53-mediated tumor surveillance system, p53 induces apoptosis or replicative senescence in oncogene-expressing cells, resulting in elimination of such cells. In this context, we previously found that Noxa and Puma synergistically induce apoptosis. Here, we found the adenovirus oncogene E1A to induce p53-dependently expression of Puma, but not Noxa. The induced Puma associates with antiapoptotic Bcl-2 protein Mcl-1, accompanied by accumulated Mcl-1 protein on mitochondria. Moreover, E1A also reduces expression of the antiapoptotic Bcl-2 protein Bcl-X(L). In contrast, the DNA-damaging agent adriamycin induces Noxa expression in E1A-expressing cells. Interestingly, Mcl-1 knockdown itself induced apoptosis in E1A-expressing MEFs. Furthermore, Noxa displaced Puma's association with Mcl-1, accompanied by Mcl-1 degradation and apoptosis induction by activating mitochondrial apoptotic executers Bax and Bak. These results suggest that p53-induced apoptosis in oncogene-expressing cells is regulated by differential induction and sequential activation of Noxa and Puma. Accumulated Puma by oncogene enhances susceptibility to apoptosis through "catch" in mitochondria by Mcl-1. Subsequently, in response to DNA-damage, Noxa efficiently induces apoptosis by "release" of Puma from Mcl-1. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.09.036

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Bone homeostasis is maintained by a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts. Since excessive osteoclast activity is implicated in pathological bone resorption, understanding the mechanism underlying osteoclast differentiation, function and survival is of both scientific and clinical importance. Osteoclasts are monocyte/macrophage lineage cells with a short life span that undergo rapid apoptosis, the rate of which critically determines the level of bone resorption in vivo. However, the molecular basis of rapid osteoclast apoptosis remains obscure. Here we report the role of a BH3-only protein, Noxa (encoded by the Pmaip1 gene), in bone homeostasis using Noxa-deficient mice. Among the Bcl-2 family members, Noxa was selectively induced during osteoclastogenesis. Mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts. Noxa deficiency did not have any effect on the number of osteoclast precursor cells or the expression of osteoclast-specific genes, but led to a prolonged survival of osteoclasts. Furthermore, adenovirus-mediated Noxa overexpression remarkably reduced bone loss in a model of inflammation-induced bone destruction. This study reveals Noxa to be a crucial regulator of osteoclast apoptosis, and may provide a molecular basis for a new therapeutic approach to bone diseases. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.06.040

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Enhanced glycolysis is important for oncogenesis and for the survival and proliferation of cancer cells in the tumor microenvironment. Recent studies have also shown that proinflammatory cytokine signaling, such as that mediated by nuclear factor κB and signal transducer and activator of transcription 3 (STAT3), is important for the generation of inflammation-associated tumors. However, the link between inflammation and enhanced glycolysis has not been identified. In the present study, we found that the proinflammatory cytokine interleukin (IL)-6 enhanced glycolysis in mouse embryonic fibroblasts and human cell lines. Moreover, STAT3 activated by IL-6 enhanced the expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase-3 (PFKFB3). Ectopic expression of PFKFB3 enhanced glycolysis, suggesting that the IL-6-STAT3 pathway enhances glycolysis through the induction of these enzymes. Our findings may provide a novel mechanism for inflammation-associated oncogenesis.

DOI： 10.1272/jnms.77.97

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Oxidative stress induces apoptosis or necrosis of many cell types, which can cause tissue injury. Hydrogen peroxide (H(2)O(2)) induced apoptotic death of Jurkat cells. This effect was inhibited by overexpression of human Bcl-2, by silencing of cytochrome c, and by ablation of Bax/Bak, indicating that H(2)O(2)-induced apoptosis was mediated by the mitochondrial pathway in Jurkat cells. Treatment with H(2)O(2) caused an increase of Noxa protein, via activating transcription factor 4-dependent accumulation of Noxa mRNA and inhibition of Noxa protein degradation. H(2)O(2)-induced apoptosis was strongly suppressed by silencing of Noxa, indicating that Noxa plays a crucial role in this form of apoptosis.

DOI： 10.1016/j.febslet.2010.01.026

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

BACKGROUND & AIMS: The molecular mechanisms of lymphoproliferation associated with the disruption of interferon (IFN) signaling and chronic hepatitis C virus (HCV) infection are poorly understood. Lymphomas are extrahepatic manifestations of HCV infection; we sought to clarify the molecular mechanisms of these processes. METHODS: We established interferon regulatory factor-1-null (irf-1(-/-)) mice with inducible and persistent expression of HCV structural proteins (irf-1/CN2 mice). All the mice (n = 900) were observed for at least 600 days after Cre/loxP switching. Histologic analyses, as well as analyses of lymphoproliferation, sensitivity to Fas-induced apoptosis, colon), formation, and cytokine production, were performed. Proteins associated with these processes were also assessed. RESULTS: Irf-1/CN2 mice had extremely high incidences of lymphomas and lymphoproliferative disorders and displayed increased mortality. Disruption of irf-1 reduced the sensitivity to Fas-induced apoptosis and decreased the levels of caspases-3/7 and caspase-9 messenger RNA species and enzymatic activities. Furthermore, the irf-1/CN2 mice showed decreased activation of caspases-3/7 and caspase-9 and increased levels of interleukin (IL)-2, IL-10, and Bcl-2, as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes. IL-2 and IL-10 were induced by the HCV core protein in splenocytes. CONCLUSIONS: Disruption of IFN signaling resulted in development of lymphoma, indicating that differential signaling occurs in lymphocytes compared with liver. This mouse model, in which HCV expression and disruption of IFN signaling synergize to promote lymphoproliferation, will be an important tool for the development of therapeutic agents that target the lymphoproliferative pathway.

DOI： 10.1053/j.gastro.2009.03.061

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Interferons-alpha/beta, which are produced upon viral infection, are key soluble factors for the establishment of an antiviral state, but are also produced at low levels in the absence of infection. Herein, we demonstrate that a weak signal by these constitutively produced IFN-alpha/beta show a preventive role in cellular transformation. Ifnar1-deficient (Ifnar1(-/-)) MEF, which are devoid of IFN-alpha/beta signal, undergo a spontaneous transformation during long-term cell culture. Similar to Irf1(-/-) MEF, primary Ifnar1(-/-) MEF become tumorigenic in nude mice by the expression of activated c-Ha-Ras oncoprotein. However, Ifnar1(-/-) MEF do not show any abnormal growth properties. A similar observation is made in Ifnb(-/-) MEF that fail to produce constitutive IFN-alpha/beta, whereas such a transforming property is not found in MEF that lack any of the IFN receptor downstream molecules including Stat1, IRF9 and IRF1. Furthermore, Ifnar1(-/-) mice develop chemically-induced skin papilloma more severely than wild-type mice. In addition, the expression levels of IFNAR1 mRNA are significantly decreased in human gastric cancer tissues. These results suggest a cell-intrinsic role of the weak signal by constitutively produced IFN-alpha/beta to prevent cells from transformation, which may be mediated by a hitherto-unknown pathway(s) downstream of the IFN-alpha/beta receptor. (Cancer Sci 2009; 100: 449-456).

DOI： 10.1111/j.1349-7006.2008.01051.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

The I kappa B kinase (IKK)-NF-kappa B pathway plays a critical role in oncogenesis. Recently, we have shown that p53 regulates glucose metabolism through the IKK-NF-kappa B pathway and that, in the absence of p53, the positive feedback loop between IKK-NF-kappa B and glycolysis has an integral role in oncogene-induced cell transformation. Here, we demonstrate that IKK beta, a component of the IKK complex, was constitutively modified with O-linked beta-N-acetyl glucosamine (O-GlcNAc) in both p53-deficient mouse embryonic fibroblasts (MEFs) and transformed human fibroblasts. In p53deficient cells, the O-GlcNAcylated IKK beta and the activating phosphorylation of IKK were decreased by p65/NF-kappa B knockdown or glucose depletion. We also found that high glucose induced the O-GlcNAcylation of IKK beta and sustained the TNF alpha-dependent IKK beta activity. Moreover, the O-GlcNAcase inhibitor streptozotocin intensified O-GlcNAcylation and concomitant activating phosphorylation of IKK beta. Mutational analysis revealed that O-GlcNAcylation of IKK beta occurred at Ser 733 in the C-terminal domain, which was identified as an inactivating phosphorylation site, suggesting that IKK beta O-GlcNAcylation regulates its catalytic activity. Taken together, we propose a novel mechanism for the enhancement of NF-kappa B activity by loss of p53, which evokes positive feedback regulation from enhanced glucose metabolism to IKK in oncogenesis.

DOI： 10.1073/pnas.0813210106

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

E2Fs are key regulators of cell-cycle progression, and their transcriptional activities are regulated by histone acetyltransferases (HATs). Retinoblastoma (Rb) family proteins (pRb, p107 and p130) bind to E2Fs and inhibit their transcriptional activities by disrupting HAT binding and recruitment of histone deacetylases. In this study, we show that I kappa B kinases (IKK alpha or IKK beta) activation inhibits cell growth and E2F-dependent transcription in normal human fibroblasts. The inhibition of E2F by IKKs was not observed in cells lacking nuclear factor (NF)-kappa B/p65; however, it was observed in cells lacking three Rb family genes. p65 disrupted the physical interaction between activator E2Fs (F2F1, E2F2 and E2F3) and the HAT cofactor transactivation/transformation-domain associated protein, resulting in a reduction in E2F-responsive gene expression. Furthermore, IKK alpha and IKK beta directly phosphorylated E2F4, resulting in nuclear accumulation and enhanced DNA binding of the E2F4/p130 repressor complex. Our study describes a novel growth inhibitory system that functions by Rb-independent suppression of E2Fs by the IKK/NF-kappa B signaling pathway.

DOI： 10.1038/onc.2008.184

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

NF-kappa B plays an important role in oncogenesis. Recently, we have demonstrated that loss of p53 function enhances DNA binding and transcriptional activities of NF-kappa B via IKK alpha and IKK beta, and that glycolysis, activated by NF-kappa B, has an integral role in oncogene-induced cell transformation. Here, we show that ectopically expressed p53 induces acetylation and phosphorylation at Ser 536 of p65, an NF-kappa B component, and enhances DNA-binding activity of NF-kappa B. However, activated p53 suppresses transcriptional activity of NF-kappa B. Under non-stimulating conditions, p65 formed a complex with IKK alpha and IKK beta. Activated p53 bound to p65 on DNA and disrupted binding of p65 to IKK beta. Moreover, histone H3 kinase activity, which requires transcriptional activation of NF-kappa B, was diminished by p53. Thus, activated p53 may suppress transcriptional activity of NF-kappa B through inhibition of IKK and histone H3 kinase on DNA, suggesting a novel p53-mediated suppression system for tumorigenesis. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2008.05.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Cancer cells use aerobic glycolysis preferentially for energy provision(1,2) and this metabolic change is important for tumour growth(3,4). Here, we have found a link between the tumour suppressor p53, the transcription factor NF-kappa B and glycolysis. In p53-deficient primary cultured cells, kinase activities of IKK alpha and IKK beta and subsequent NF-kappa B activity were enhanced. Activation of NF-kappa B, by loss of p53, caused an increase in the rate of aerobic glycolysis and upregulation of Glut3. Oncogenic Ras-induced cell transformation and acceleration of aerobic glycolysis in p53-deficient cells were suppressed in the absence of p65/ NF-kappa B expression, and were restored by GLUT3 expression. It was also shown that a glycolytic inhibitor diminished the enhanced IKK activity in p53-deficient cells. Moreover, in Ras-expressing p53-deficient cells, IKK activity was suppressed by p65 deficiency and restored by GLUT3 expression. Taken together, these data indicate that p53 restricts activation of the IKK - NF-kappa B pathway through suppression of glycolysis. These results suggest that a positivefeedback loop exists, whereby glycolysis drives IKK - NF-kappa B activation, and that hyperactivation of this loop by loss of p53 is important in oncogene- induced cell transformation.

DOI： 10.1038/ncb1724

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of Smoothened (Smo), a transducer of the Hh signaling pathway, inhibit the accumulation of the tumor suppressor protein p53. This inhibition was also observed in the presence of Hh ligand or with the overexpression of the transcription factors Gli1 and Gli2, downstream effectors of Smo, indicating that this inhibition is specific for the Hh pathway. We also report that Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination. Furthermore, Hh signaling induced the phosphorylation of human Mdm2 protein on serines 166 and 186, which are activating phosphorylation sites of Mdm2. Smo mutants enhanced the proliferation of mouse embryonic fibroblasts (MEFs) while inducing a DNA-damage response. Moreover, Smo partially inhibited p53-dependent apoptosis and cell growth inhibition in oncogene-expressing MEFs. We also found that accumulation of p53 is inhibited by Hh signaling in several human cancer cell lines. Therefore, the Hh pathway may be a powerful accelerator of oncogenesis by activating cell proliferation and inhibiting the p53-mediated anti-cancer barrier induced by oncogenic stress.

DOI： 10.1073/pnas.0712216105

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INFORMA HEALTHCARE  

The expression of p53-target genes encoding the proapoptotic factor Noxa, but not PUMA, was not induced by p53 in HCT116 and SW480 cells, which show resistance to apoptosis in response to p53 overexpression. The lack of p53 inducibility of Noxa was restored by treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-CdR). Furthermore, p53 induced apoptosis in HCT116 and SW480 cells treated with 5-aza-CdR. Moreover, the inhibition of Noxa expression by RNAi in 5-aza-CdR-treated HCT116 cells resulted in the partial inhibition of p53-induced apoptosis. These results suggest that epigenetic cancer therapy is possible for some cancers in combination with forced p53 activation.

DOI： 10.1080/07357900701840212

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

One critical tumor-suppressive function of p53 is the induction of apoptosis in oncogene-expressing cells. In this context, p53-inducible genes encoding the BH3-only proteins of the Bcl-2 family, Noxa and Puma, were identified. Gene knockout studies revealed that both Noxa and Puma are involved in apoptosis induction in oncogene-expressing cells. BH3-only proteins induce apoptosis, and activate the downstream apoptosis effectors Bax and Bak. In this study, we found that Noxa and Puma synergistically activate Bax and Bak, and induce apoptosis. Although Noxa activates Bak by inactivating Mcl-1 and Bcl-XL, gene knockdown studies revealed that neither Mcl-1 nor Bcl-XL is involved in this synergism. Moreover, Puma, but not Noxa, directly activated Bax in the absence of Bak, and Noxa enhanced Puma-mediated Bax activation in Bak-deficient cells. These results suggest the existence of a novel regulatory pathway for Noxa-mediated apoptosis. Although we detected synergistic induction of apoptosis by Noxa and Bim, a tumor suppressive transcriptional factor FoxO3-inducible protein, no such synergism was observed for other pairs of BH3-only proteins. Bim and Bid, or Bim and Puma. From these results, it can be considered that p53 carefully controls apoptosis by allowing two molecules to share full ability to induce apoptosis.

DOI： 10.1272/jnms.74.148

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Medical Association of Nippon Medical School  

DOI： 10.1272/jnms.74.384

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

The tumor suppressor p53 exerts its versatile function to maintain the genomic integrity of a cell, and the life of cancerous cells with DNA damage is often terminated by induction of apoptosis. We studied the role of Noxa, one of the transcriptional targets of p53 that encodes a proapoptotic protein of the Bcl-2 family, by the gene-targeting approach. Mouse embryonic fibroblasts deficient in Noxa [Noxa(-/-) mouse embryonic fibroblasts (MEFs)] showed notable resistance to oncogene-dependent apoptosis in response to DNA damage, which was further increased by introducing an additional null zygosity for Bax. These MEFs also showed increased sensitivity to oncogene-induced cell transformation in vitro. Furthermore, Noxa is also involved in the oncogene-independent gradual apoptosis induced by severe genotoxic stresses, under which p53 activates both survival and apoptotic pathways through induction of p21(WAF1/Cip) and Noxa, respectively. Noxa(-/-) mice showed resistance to X-ray irradiation-induced gastrointestinal death, accompanied with impaired apoptosis of the epithelial cells of small intestinal crypts, indicating the contribution of Noxa to the p53 response in vivo.

DOI： 10.1101/gad.1103603

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC  

Efficient IFN-alpha/beta gene induction in virus-infected cells is an event central to innate immunity, in which the transcription factor IRF-7 plays a critical role together with IRF-3. Unlike IRF-3, IRF-7 is short-lived and its gene expression is dependent on IFN-alpha/beta signalling; hence, the signal-dependent enhancement of IRF-7 gene induction during viral infection is essential for positive-feedback regulation of IFN-alpha/beta gene induction. Here, we provide evidence that constitutive, IRF-3/IRF-7-independent production of IFN-alpha/beta in uninfected cells is critical for setting the IRF-7 expression levels, determining whether or not the positive-feedback mechanism will operate effectively upon viral infection. In fact, spleen cells are more dependent than fibroblasts on this mechanism; the IFN-alpha/beta gene induction is impaired more severely by blocking the IRF-7 induction pathway than by introducing an IRF-3 null mutation. Thus, the constitutive IFN-alpha/beta signal provides a foundation for the IRF-7-mediated enhancement of its own production in response to virus infection. (C) 2001 Academic Press.

DOI： 10.1006/bbrc.2001.5159

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記述言語：英語   出版者・発行元：ELSEVIER SCI LTD  

Interferon regulatory factors (IRFs) were initially identified as regulators of IFN-alpha/beta genes and to date nine members have been determined in human and mouse. They share a conserved DNA-binding domain in the N-terminal portion that recognizes similar DNA sequences. Despite their similar DNA binding specificity, the IRFs show diverse functions in response to extra cellular stimuli. Although the study of IRFs was started with respect to regulation of the IFN-alpha/beta gene expression, recent studies have revealed other aspects of IRF functions. In this review, we summarize our current knowledge of the functions of IRF family members revealed by our gene targeting study in mice, focusing on the regulation of the IFN system. (C) 2001 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/s1359-6101(00)00032-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC  

During viral infection, interferon-alpha/beta (IFN-alpha/beta) and many IFN-inducible genes are induced to elicit antiviral responses of the host. Using cells with a gene disruption(s) for the IRF family of transcription factors, we provide evidence that these genes, containing similar IRF-binding cis-elements, are classified into distinct groups, based on the gene induction pathway(s), The IFN-beta gene induction is dependent on either IRF-3 or IRF-7, whereas induction of the IFN-alpha gene family is IRF-7-dependent. On the other hand, ISG15, ISG54 and IP-10 are induced by either IRF-3 or IFN stimulated gene factor 3 (ISGF3). We also show that another group of genes is totally dependent on ISGF3, Thus, during viral infection, a given gene responds either directly to a virus or virus-induced IFN-alpha/beta or both through distinct pathways, The differential utilization of these induction pathways for these genes during viral infection may reflect their distinct functional roles in the efficient antiviral response. (C) 2001 Academic Press.

DOI： 10.1006/bbrc.2001.4913

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-α/β signalling complex, generated by spontaneously produced IFN-α/β, in efficient IFN-γ signalling. Results: In the present study, we have demonstrated that the IFN-α/β signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-α/β signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-α/β stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity. Conclusions: The constitutive weak IFN-α/β signal provides a foundation for strong cellular responses to IL-6, IFN-γ, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor sub-units, which may represent a 'receptosome'-like structure, allowing the unique signalling cross talks to occur.

DOI： 10.1046/j.1365-2443.2001.00448.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Natural killer (NK) cells play an important role in early defense against viral infection. The cytotoxic activity of NK cells is increased by interferon-α/β (IFN-α/β), produced en masse in virally infected cells. However, the mechanism(s) by which IFN-α/β contribute to the NK-cell-mediated antiviral response is not well understood. Here we provide evidence that the cytotoxicity of NK cells is enhanced by IFN-α/β through induction of TNF-related apoptosis-inducing ligand (TRAIL). Isolation and analysis of the murine TRAIL promoter revealed the presence of an IFN-stimulated response element (ISRE), which binds to the transcription factor ISGF3 (interferon stimulated gene factor-3). This promoter is indeed activated by IFN-β in ISGF3-dependent manner. We also show that virally infected cells, but not uninfected cells, are susceptible to TRAIL-mediated cytotoxicity in vitro, and that the TRAIL expressed in NK cells is indeed crucial in limiting virus replication in vivo. Thus, our study reveals a new molecular link between IFN-α/β signaling and activation of NK cells in antiviral response of the host.

DOI： 10.1002/1521-4141(200111)31:11<3138::AID-IMMU3138>3.0.CO;2-B

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記述言語：英語   出版者・発行元：ANNUAL REVIEWS  

Interferon regulatory factors (IRFs) constitute a family of transcription factors that commonly possess a novel helix-turn-helix DNA-binding motif. Following the initial identification of two structurally related members, IRF-1 and IRF-2, seven additional members have now been reported. In addition, virally encoded IRFs, which may interfere with cellular IRFs, have also been identified. Thus far, intensive functional analyses have been done on IRF-1, revealing a remarkable functional diversity of this transcription factor in the regulation of cellular response in host defense. Indeed, IRF-1 selectively modulates different sets of genes, depending on the cell type and/or the nature of cellular stimuli, in order to evoke appropriate responses in each. More recently, much attention has also been focused on other IRF family members. Their functional roles, through interactions with their own or other members of the family of transcription factors, are becoming clearer in the regulation of host defense, such as innate and adaptive immune responses and oncogenesis.

DOI： 10.1146/annurev.immunol.19.1.623

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Induction of the interferon (IFN)-alpha/beta gene transcription in virus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-alpha/beta gene expression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered. Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested. In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinct roles of the two factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response.

DOI： 10.1016/s1074-7613(00)00053-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

A novel gene, Reprimo, in which induction in cells exposed to X-irradiation is dependent on p53 expression, has been isolated. Ectopic p53 expression results in the induction of its mRNA. Reprimo is a highly glycosylated protein and, when ectopically expressed, it is localized in the cytoplasm and induces G(2) arrest of the cell cycle. In the arrested cells, both Cdc2 activity and nuclear translocation of cyclin El are inhibited, suggesting the involvement of Reprimo in the Cdc2.cyclin B1 regulation pathway. Thus, Reprimo may be a new member involved in the regulation of p53-dependent G(2) arrest of the cell cycle.

DOI： 10.1074/jbc.C000235200

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DOI： 10.1126/science.288.5475.2357

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DOI： 10.1126/science.288.5468.1053

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD  

We study a family of transcription factors, the interferon regulatory factors (IRFs) as originally identified in the context of the regulation of type-I interferon (IFN-alpha /beta) system. Most notably, studies on IRF-1 have revealed its remarkable functional diversity in the regulation of cellular responses of host defense, including oncogenesis. The IRF family has now expanded to nine members, and gene disruption studies have revealed critical involvement of some of the members in the regulation of cell growth and oncogenesis, In this review, we summarize our current knowledge on the involvement of members of the IRF family members, in particular; IRF-1, in oncogenesis.

DOI： 10.1006/scbi.2000.0310

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induction of the interferon (IFN)-α/β gene transcription in virus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-α/β gene expression levels are reduced and the spectrum of the IFN-α mRNA subspecies altered. Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested. In these cells, a normal profile of IFN-α/β mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinct roles of the two factors, which together ensure the transcriptional efficiency and diversity of IFN-α/β genes for the antiviral response.

DOI： 10.1016/S1074-7613(00)00053-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WALTER DE GRUYTER & CO  

The interferon-stimulated gene factor 3 (ISGF3) transcription factor has been extensively studied in the context of the type I interferon (IFN-alpha/beta)-mediated antiviral response; it consists of the major DNA-binding component p48, and the signal transducers and activators of transcription (Stat)1 and Stat2. We show here that type II IFN (IFN-gamma) can also invoke the activation of ISGF3 in mouse primary embryonic fibroblasts. In fact, the two Stat proteins were tyrosine phosphorylated in IFN-gamma stimulated cells. Our present findings reveal an additional mechanism by which these two distinct types of cytokines, IFN-alpha/beta and -gamma, can commonly elicit antiviral activities.

DOI： 10.1515/BC.1999.087

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COLD SPRING HARBOR LAB PRESS  

The transcription factor IRE-I has been implicated in tumor suppression: IRF-1 suppresses cell transformation and mediates apoptosis in vitro. Here we show that the loss of IRF-1 alleles per se has no effect on spontaneous turner development in the mouse but dramatically exacerbates previous tumor predispositions caused by the c-Ha-ras transgene or by nullizygosity for p53. Grossly altered tumor spectrum, as compared to p53-null mice, was also observed in mice lacking both IRE-I and p53, and cells from these mice show significantly higher mutation rate. Our results suggest that IRF-1 is a new member of the tumor susceptibility genes.

DOI： 10.1101/gad.13.10.1240

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Two distinct types of interferon, IFN-alpha/beta and IFN-gamma, commonly exhibit antiviral activities by transmitting signals to the interior of the cell via their homologous receptors, Receptor stimulation results in the activation of distinct combinations of Janus family protein tyrosine kinases (Jak PTKs); Jak1/Tyk2 and Jak1/Jak2 for IFN-alpha/beta and IFN-gamma, respectively. Jak PTK activation by these IFNs is commonly followed by tyrosine phosphorylation of the transcription factor Stat1 at Y701, which is essential for dimerization, translocation to the nucleus and DNA-binding activity. To gain full transcriptional activity, Stat1 also requires serine phosphorylation at S727, In this paper we demonstrate that Pyk2, which belongs to another PTK family, is critical for the Jak-mediated MAPK and Stat1 activation by IFN-gamma, but not IFN-alpha, Pyk2 is selectively associated with Jak2 and activated by IFN-gamma. Overexpression of PKM, a dominant interfering form of Pyk2, in NIH 3T3 cells results in a strong inhibition of the IFN-gamma-induced activation of Erk2, serine phosphorylation of Stat1 and Stat1-dependent gene transcription. Finally, the antiviral action of IFN-gamma, but not IFN-alpha, is severely impaired by PKM overexpression. Thus, the two types of IFN may utilize distinct Jak-mediated Erk2, and possibly other MAPK activation pathways for their antiviral action.

DOI： 10.1093/emboj/18.9.2480

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COLD SPRING HARBOR LAB PRESS  

DOI： 10.1101/sqb.1999.64.465

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The interferon regulatory factor (IRF) family of transcription factors regulate the interferon (IFN) system, among which IRF-3 is involved in the virus-induced IFN-beta gene expression. Here me show that another member IRF-7 is critical for the IFN-alpha gene induction. Unlike the IRF-3 gene, the IRF-7 gene is induced by IFNs through activation of the ISGF3 transcription factor, and IRF-7 undergoes virus-induced nuclear translocation. In cells lacking p48, an essential component of IFN stimulated gene factor 3 (ISGF3), ectopic expression of IRF-7 but not IRF-3 can rescue the deficiency to induce IFN-alpha genes. These results indicate that IRF-7 is a key factor in the positive feedback regulation of IFN-alpha/beta production. (C) 1998 Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(98)01514-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JOHN LIBBEY EUROTEXT LTD  

Interferon regulatory factor-1 (IRF-1) is a transcriptional activator which was originally identified as the regulator of the type I interferon (IFN-alpha/beta) gene expression. Subsequent studies have revealed that IRF-1 is involved in a wide spectrum of the host defense mechanisms, including the antiviral response by IFNs. IRF-1 has also been shown to regulate a variety of cytokines and their target genes, thereby contributing to the development and function of the Th1-type immune response. Furthermore, IRE-I is a critical regulator of cell growth and death, and its inactivation accelerates cell transformation. IRF-1 may be a prototypical example of a transcription factor which can selectively modulate distinct sets of genes depending on the cell type and/or nature of the cellular stimuli, so as to evoke appropiate response in each.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER  

Complex cellular responses are often coordinated by a genetic regulatory network in which a given transcription factor controls the expression of a diverse set of target genes. Interferon regulatory factor (IRF)-1 and IRF-2 have originally been identified as a transcriptional activator and repressor, respectively, of the interferon-beta (IFN-beta) as well as of IFN-inducible genes. However, these factors have since been shown to modulate not only the cellular response to IFNs, but also cell growth, susceptibility to transformation by oncogenes, induction of apoptosis, and development of the T cell immune response. Furthermore, the evidence suggests that deletion and/or inactivation of the IRF-1 gene may be a critical step in the development of some human hematopoietic neoplasms. Subsequently, these factors have been shown to constitute a family of transcription factors, termed the IRF-family. Recent studies indicate that other IRF family members also involve the regulation of the IFN system and cell transformation. The IRF-family may be examples of transcription factors which can selectively modulate several sets of genes depending on the cell type and/or nature of the cellular stimuli, so as to evoke host defense mechanisms against infection and oncogenesis. (C) Societe francaise de biochimie et biologie moleculaire/Elsevier, Paris.

DOI： 10.1016/s0300-9084(99)80017-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Loss of heterozygosity (LOH) observed in human tumors strongly suggests the existence of (a) tumor-suppressor gene(s) at the concerned locus. A series of studies has revealed that LOH on the long arm of chromosome 5 (5q) frequently occurs in differentiated gastric adenocarcinomas. Furthermore, it has been shown that the interferon regulatory factor-1 (IRF-1) locus on chromosome 5q31.1 is one of the common minimal regions of LOH in these cancers. IRF-1 is a transcriptional activator that shows tumor-suppressor activity in the mouse. In the present study, we examined the sequence of the IRF-1 gene in 9 cases of histologically differentiated gastric adenocarcinomas, all of which exhibited LOH at the IRF-1 locus. We identified a mis-sense mutation in the residual allele in one case. This mutated form of IRF-1 showed markedly reduced transcriptional activity. In addition, overexpression of wild-type IRF-1 induced cell-cycle arrest, whereas such activity was attenuated in the mutant IRF-1. These results suggest that the loss of functional IRF-1 is critical for the development of human gastric cancers. Int. J. Cancer 77:522-527, 1998. (C) 1998 Wiley-Liss, Inc.

DOI： 10.1002/(sici)1097-0215(19980812)77:4<522::aid-ijc8>3.0.co;2-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CHURCHILL LIVINGSTONE  

Transcriptional activator interferon regulatory factor (IRF)-1 and repressor IRF-2 are known to play a critical role in the regulation of interferon (IFN) responses and oncogenesis in fibroblasts, Although these two factors are expressed in many tissues, including the brain, the role of IRFs in the central nervous system (CNS) has not been elucidated. We analysed a medulloblastoma cell line, ONS-76, as a CNS-derived model system and generated its derivatives, R1 and R2 cells, which constitutively expressed each mouse IRF-1 and IRF-2 cDNA at high levels. By viral infection, R1 and R2 cells showed IFN-beta gene expression 3 h earlier than the control ONS-76 (C-76) cells, with 2.46- and 2.24-fold increase in IFN-beta production respectively. In the presence of cycloheximide, virally induced IFN-beta gene expression of C-76 cells was suppressed, whereas R1 and R2 cells produced IFN-beta 7.5- and 2.2-fold higher than C-76 cells respectively. On the other hand, induction of IFN-inducible genes was enhanced in R1 cells but was suppressed in R2 cells compared with C-76 cells. These results demonstrate that IRF-1 and IRF-2 may play an important role in the regulation of IFN-beta and IFN-inducible genes and that IRF-2 may have dual functions as an activator and repressor in CNS-derived cells.

DOI： 10.1038/bjc.1998.351

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MARY ANN LIEBERT INC PUBL  

2',5'-Oligoadenylate synthetase (2'5'OAS), an enzyme induced by interferon (IFN), is physiologically produced in IFN-untreated normal healthy mice, The enzyme is localized mainly in the epithelium of the digestive tract, reproductive organs, and the choroid plexus in the brain, 2'5'OAS is also detected in oocytes in the ovary and in neurons and glial cells of both the telencephalon and cerebellum, Here, we examined the role of p48 (ISGF3 gamma), a component of IFN-stimulated gene factor 3 (ISGF3), in the physiologic production of 2'5'OAS using p48-deficient mice generated by gene targeting, In the p48-deficient mice, the physiologic production of 2'5'OAS localized in the following cells was severely impaired: hepatocytes, Kupffer cells, splenocytes, epithelium of the large intestine, oviduct, and uterus, and neurons and glial cells in both the telencephalon and cerebellum, The results show that 2'5'OAS in these cells is induced physiologically through a pathway including p48, However, the production of 2'5'OAS in oocytes was not affected in the p48-deficient mice, indicating that oocyte 2'5'OAS is produced through a p48-independent pathway, A possible function of the GAS sequence found in the promoter region of the 2'5'OAS gene to which Stat6 may bind also is discussed.

DOI： 10.1089/jir.1998.18.181

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

The virus-induced activation of interferon alpha/beta (IFN-alpha/beta) gene transcription is essential for host defense. The IFN-beta promoter is controlled primarily by the virus-inducible enhancer elements, the IRF-Es. Here se show that IRF-3, an IRF family transcription factor, translocates to the nucleus from the cytoplasm upon virus infection in NIH/3T3 cells. The nuclear IRF-3 is phosphorylated, interacts with the co-activators CBP/p300, and binds specifically to the IFN-beta IRF-E. Furthermore, overexpression of IRF-3 causes a marked increase in virus-induced IFN-beta mRNA expression, Thus, IRF-3 is a candidate transcription factor mediating the activation of the IFN-beta gene. (C) 1998 Federation of European Biochemical Societies.

DOI： 10.1016/s0014-5793(98)00210-5

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DOI： 10.1046/j.1365-2443.1998.00164.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：STOCKTON PRESS  

Interferon regulatory factor-1 (IRF-1) acts as a transcriptional activator in the interferon system and as a tumor suppressor. The loss of functional IRF-1 has been observed in a significant number of patients with myelodysplastic syndrome (MDS) and leukemia, suggesting a potentially critical role of IRF-1 in human oncostasis. Here we report an alternative mechanism by which IRF-1 may be inactivated. We purified an IRF-1 association molecule which was revealed to be identical to a nuclear factor nucleophosmin (NPM)/B23/numatrin. Functional analysis showed that NPM inhibited the DNA-binding and transcriptional activity of IRF-1. Moreover, NPM was overexpressed in several clinical leukemia samples and human-derived leukemia cell lines. Finally, overexpression of NPM in NIH3T3 cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivating IRF-1-dependent anti-oncogenic surveillance in human cancer development.

DOI： 10.1038/sj.onc.1201286

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DOI： 10.1016/s0304-419x(97)00014-0

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DOI： 10.1016/S0962-8924(97)82668-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

Lymphocytes are highly sensitive to DNA damage-induced apoptosis. In thymocytes, the tumor suppressor p53 has been shown to be required for this type of apoptosis. However an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogenically activated mature T lymphocytes. By using mice with a null mutation in the IRF-1 gene, we revealed that DNA damage-induced apoptosis in the latter cell type is dependent on the anti-oncogenic transcription factor interferon regulatory factor-1 (IRF-1). Thus two different anti-oncogenic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. Furthermore, we found that mitogen induction of the interleukin-1β-converting enzyme (Ice) gene, a mammalian homolog of the Caenorhabditis elegans cell death gene ced-3, is also IRF-1-dependent. An IRF-1 binding sequence was identified in the 5′ flanking region of the Ice gene. In addition, ectopic overexpression of IRF-1 results in the activation of the endogenous Ice gene and enhances the sensitivity of cells to radiation-induced apoptosis. Thus, induction of Ice gene may be involved in IRF-1 dependent DNA damage-induced apoptosis in activated mature T lymphocytes.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MACMILLAN MAGAZINES LTD  

NORMALLY growing cells promptly cease DNA synthesis when exposed to genotoxic stresses, such as radiation, and this cell-cycle arrest prevents the accumulation of mutations(1,2). The transcription factor interferon regulatory factor (IRF)-1 is essential for the regulation of the interferon system(3-5), inhibits cell growth, and manifests tumour-suppressor activities(6,7). Here we show that mouse embryonic fibroblasts (EFs) lacking LRF-1 are deficient in their ability to undergo DNA-damage-induced cell-cycle arrest. A similar phenotype has been observed in EFs lacking the tumour suppressor p53 (refs 8, 9), although the expression of IRF-1 and p53 are independent of one another. Furthermore, we show that transcriptional induction of the gene encoding p21 (WAF1, CIP1)(10-12), a cell-cycle inhibitor, by gamma-irradiation is dependent on both p53 and IRF-1, and that the p21 promoter is activated, either directly or indirectly, by both in a transient cotransfection assay. These two tumour-suppressor transcription factors therefore converge functionally to regulate the cell cycle through the activation of a common target genes.

DOI： 10.1038/382816a0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MACMILLAN MAGAZINES LTD  

LYMPHOCYTES are particularly susceptible to DNA damage-induced apoptosis, a response which may serve as a form of 'altruistic suicide' to counter their intrinsic high potential for mutation and clonal expansion(1). The tumour suppressor p53 has been shown to regulate this type of apoptosis in thymocytes(2,3), but an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogen-activated mature T lymphocytes(4). Here we show that DNA damage-induced apoptosis in these T lymphocytes is dependent on the antioncogenic transcription factor interferon regulatory factor (IRF)-1 (refs 5-7). Thus two different anti-oncogenic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. We also show that mitogen induction of the interleukin-1 beta converting enzyme (ICE) gene(8-10), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, is IRF-1-dependent. Ectopic overexpression of IRE-1 results in the activation of the endogenous gene for ICE and enhances the sensitivity of cells to radiation-induced apoptosis.

DOI： 10.1038/376596a0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：STOCKTON PRESS  

The transcription factor IRF-1 has been shown to function as a tumor suppressor. Here we report that a significant proportion of the IRF-1 mRNA detected in normal human hematopoietic cells and cultured cell lines lacks exon 2 (containing the AUG initiation codon) and 3 as a result of exon skipping. Surprisingly, when we examined the bone marrow and peripheral mononuclear cells from patients with myelodysplastic syndrome (MDS) or leukemia secondary to MDS, we could still detect the exon-skipped form but little or none of the intact IRF-1 mRNA. This appears to be the result of accelerated exon skipping since we could find no mutations within the exons and splicing junctions from these patients. The exon-skipped form of IRF-1 lacking exons 2 and 3 displayed neither DNA binding nor tumor suppressive activities. Thus this accelerated exon skipping may cause the inactivation of IRF-1 and thereby contribute to the development of human hematopoietic malignancies.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI IRELAND LTD  

The transcriptional activator IRF-1 and its antagonistic repressor IRF-2 are regulators of the interferon (IFN) system and of cell growth. Overexpression of IRF-2 leads to transformation of NIH3T3 cells, and the concomitant overexpression of IRF-1 reverts this transformed phenotype. Here we report that c-myc- of fosB-transformed rat embryonic fibroblast cells can be reverted by the introduction of the IRF-1 gene. Thus, the anti-oncogenic function of IRF-1 is not limited to only IRF-2 overexpressing cells, suggesting the broad role of IRF-1 as a tumor suppressor.

DOI： 10.1016/0304-3835(94)90318-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

The transcriptional activator interferon regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the interferon (IFN) system and of cell growth. Here we report that embryonic fibroblasts (EFs) from mice with a null mutation in the IRF-1 gene (IRF-1(-/-) mice) can be transformed by expression of an activated c-Ha-ras oncogene. This property is not observed in EFs from wild-type or IRF-2(-/-) mice but is still observed in EFs from mice deficient in both genes. The transformed phenotype of ras-expressing IRF-1(-/-) EFs could be suppressed by the expression of the IRF-1 cDNA. Thus, IRF-1 functions as a tumor suppressor. Furthermore, expression of the c-Ha-ras oncogene causes wild-type but not IRF-1(-/-) EFs to undergo apoptosis when combined with a block to cell proliferation or treated by anticancer drugs or ionizing radiation. Hence, IRF-1 may be a critical determinant of oncogene-induced cell transformation or apoptosis.

DOI： 10.1016/0092-8674(94)90132-5

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DOI： 10.1126/science.8009222

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DOI： 10.1128/mcb.13.8.4531

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DOI： 10.1126/science.8438157

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DOI： 10.1126/science.8438156

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記述言語：英語   出版者・発行元：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

DOI： 10.1016/s0065-2776(08)60877-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS LTD  

DOI： 10.1016/0022-2836(91)90873-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

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記述言語：英語   出版者・発行元：AMER SOC MICROBIOLOGY  

DOI： 10.1128/mcb.9.1.349

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/0167-4781(86)90060-6

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