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| 1.
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Zhao, Juanjuan ; Okamoto, Yasuo ; Asano, Yuya ; Ishimaru, Kazuhiro ; Aki, Sho ; Yoshioka, Kazuaki ; Takuwa, Noriko ; Wada, Takashi ; Inagaki, Yutaka ; Takahashi, Chiaki ; Nishiuchi, Takumi ; Takuwa, Yoh ; 安藝, 翔 ; 吉岡, 和晃 ; 多久和, 典子 ; 和田, 隆志 ; 髙橋, 智聡 ; 西内, 巧 ; 多久和, 陽
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金沢大学医薬保健研究域医学系<br />Idiopathic pulmonary fibrosis is a devastating disease with poor prognosis. The pathogenic role of t
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he lysophospholipid mediator sphingosine-1-phosphate and its receptor S1PR2 in lung fibrosis is unknown. We show here that genetic deletion of S1pr2 strikingly attenuated lung fibrosis induced by repeated injections of bleomycin in mice. We observed by using S1pr2 LacZ/+ mice that S1PR2 was expressed in alveolar macrophages, vascular endothelial cells and alveolar epithelial cells in the lung and that S1PR2-expressing cells accumulated in the fibrotic legions. Bone marrow chimera experiments suggested that S1PR2 in bone marrow–derived cells contributes to the development of lung fibrosis. Depletion of macrophages greatly attenuated lung fibrosis. Bleomycin administration stimulated the mRNA expression of the profibrotic cytokines IL-13 and IL-4 and the M2 markers including arginase 1, Fizz1/Retnla, Ccl17 and Ccl24 in cells collected from broncho-alveolar lavage fluids (BALF), and S1pr2 deletion markedly diminished the stimulated expression of these genes. BALF cells from bleomycin–administered wild-type mice showed a marked increase in phosphorylation of STAT6, a transcription factor which is activated downstream of IL-13, compared with saline–administered wild-type mice. Interestingly, in bleomycin–adminis-tered S1pr2 -/- mice, STAT6 phosphorylation in BALF cells was substantially diminished compared with wild-type mice. Finally, pharmacological S1PR2 blockade in S1pr2 +/+ mice alleviated bleomycin–induced lung fibrosis. Thus, S1PR2 facilitates lung fibrosis through the mechanisms involving augmentation of IL-13 expression and its signaling in BALF cells, and represents a novel target for treating lung fibrosis. © 2018 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 2.
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Kitajima, Shunsuke ; Takahashi, Chiaki ; 北嶋, 俊輔 ; 髙橋, 智聡
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金沢大学がん進展制御研究所<br />The Retinoblastoma (RB) tumor suppressor regulates G1/S transition during cell cycle progression by m
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odulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment-resistant cancers, it has become increasingly clear that, in the majority of cancers, somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene is often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates G1/S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we reported that RB inactivation enhances pro-inflammatory signaling through stimulation of the interleukin-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling. © 2017 Japanese Cancer Association.
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| 3.
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Nagata, Naoto ; Xu, Liang ; Kohno, Susumu ; Ushida, Yusuke ; Aoki, Yudai ; Umeda, Ryohei ; Fuke, Nobuo ; Zhuge, Fen ; Ni, Yinhua ; Nagashimada, Mayumi ; Takahashi, Chiaki ; Suganuma, Hiroyuki ; Kaneko, Shuichi ; Ota, Tsuguhito
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Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Howev
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er, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)–fed mice. Glucoraphanin supplementation attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in HFD-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Compared with vehicle-treated controls, glucoraphanin-treated HFD-fed mice had lower plasma lipopolysaccharide levels and decreased relative abundance of the gram-negative bacteria family Desulfovibrionaceae in their gut microbiomes. In HFD-fed mice, glucoraphanin increased energy expenditure and the protein expression of uncoupling protein 1 (Ucp1) in inguinal and epididymal adipose depots. Additionally, in this group, glucoraphanin attenuated hepatic lipogenic gene expression, lipid peroxidation, classically activated M1-like macrophage accumulation, and inflammatory signaling pathways. By promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may mitigate obesity, insulin resistance, and NAFLD.
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Hayashi, Naoyuki ; Kobayashi, Masahiko ; Shamma, Awad ; Morimura, Yoko ; Takahashi, Chiaki ; Yamamoto, Ken-ichi
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NBS1 is the causative gene product of Nijmegen breakage syndrome (NBS), a recessive genetic disorder resulting in chromo
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somal instability and immunodeficiency. We isolated DNMT1 cDNA by two-hybrid screening by using NBS1 as bait to study its function in DNA replication and damage checkpoint. DNMT1 encodes DNA methyltransferase 1, which maintains the genomic methylation pattern and also regulates the checkpoint pathway via interactions with various factors, such as CHK1, p53, Rb and ATM. The interaction between NBS1 and DNMT1 was observed under conditions of hydroxyl urea treatment, resulting in replication stall and mitomycin C treatment resulting in DNA damage. Additionally, we mapped their binding regions to the N-terminus of NBS1 (including the forkhead- associated domain) and amino acids 14011503 in the target recognition domain in the C-terminus of DNMT1. Under DNA replication stall conditions, DNMT1 was recruited to the survivin promoter by p53, and it repressed survivin expression via hetrochromatin formation; this regulation was dependent on the NBS1 genotype. These results suggest that DNMT1 function in the regulatory response is controlled by NBS1. © The Authors 2013. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
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| 5.
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Takahashi, Chiaki ; Sasaki, Nobunari ; Kitajima, Shunsuke
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One-quarter of a century ago, identification of the human retinoblastoma gene (RB) loci proved Knudson's 'two-hit theory
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' that tumor suppressor genes exist. Since then, numerous works delineated crucial roles for the RB protein (pRB)-E2F transcription factor complex in G1-S phase transition. In addition, discovering the relationship between pRB and tissue-specific transcription factors enabled a better understanding of how cell cycle exit and terminal differentiation are coupled. Recent works provoked many exciting twists in views on pRB functions during cancer initiation and progression beyond its previously well-appreciated roles. Various mitogenic and cytostatic cellular signals appeared to modulate pRB functions and thus affect a wide variety of effector molecules. In addition, genetic studies in mice as well as other creatures incessantly force us to revise our views on pRB functions. This review will focus particularly on the roles of pRB in regulating intracellular signaling, cell metabolism, chromatin function, stem cells and cancer stem cells. © 2012 Japanese Cancer Association.
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| 6.
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Shamma, Awad ; Tagami, Yujiro ; Miki, Takao ; Kitajima, Shunsuke ; Noda, Makoto ; Obara, Takao ; Okamoto, Takahiro ; Takahashi, Chiaki
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Oncogene-induced cellular senescence is well documented, but little is known about how infinite cell proliferation induc
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ed by loss of tumor suppressor genes is antagonized by cellular functions. Rb heterozygous mice generate Rb-deficient C cell adenomas that progress to adenocarcinomas following biallelic loss of N-ras. Here, we demonstrate that pRb inactivation induces aberrant expression of farnesyl diphosphate synthase, many prenyltransferases, and their upstream regulators sterol regulatory element-binding proteins (SREBPs) in an E2F-dependent manner, leading to enhanced isoprenylation and activation of N-Ras. Consequently, elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis. © 2009 Elsevier Inc. All rights reserved.
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| 7.
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Shamma, Awad ; Suzuki, Misa ; Hayashi, Naoyuki ; Kobayashi, Masahiko ; Sasaki, Nobunari ; Nishiuchi, Takumi ; Doki, Yuichiro ; Okamoto, Takahiro ; Kohno, Susumu ; Muranaka, Hayato ; Kitajima, Shunsuke ; Yamamoto, Ken-ichi ; Takahashi, Chiaki
概要:
The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of
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this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.
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| 8.
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Salah, Mohammed ; Nishimoto, Yuuki ; Kohno, Susumu ; Kondoh, Atsushi ; Kitajima, Shunsuke ; Muranaka, Hayato ; Nishiuchi, Takumi ; Ibrahim, Ahmed ; Yoshida, Akiyo ; Takahashi, Chiaki
概要:
Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of ge
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nes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53−/−; Rbf/f, Trp53−/−; Ptenf/f, and Trp53−/−; Rbf/f; Ptenf/f prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53−/− prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.<br />Embargo Period 12 months
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| 9.
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Yoshida, Akiyo ; Kitajima, Shunsuke ; Li, Fengkai ; Cheng, Chaoyang ; Takegami, Yujiro ; Kohno, Susumu ; Wan, Yuan Song ; Hayashi, Naoyuki ; Muranaka, Hayato ; Nishimoto, Yuuki ; Nagatani, Naoko ; Nishiuchi, Takumi ; Thai, Tran C ; Suzuki, Sawako ; Nakao, Shinji ; Tanaka, Tomoaki ; Hirose, Osamu ; Barbie, David A. ; Takahashi, Chiaki
概要:
We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic
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phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.<br />Supplementary Table1 and Supplementary Table2: We offer the table data with an Excel file
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| 10.
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Miki, Takao ; Shamma, Awad ; Kitajima, Shunsuke ; Takegami, Yujiro ; Noda, Makoto ; Nakashima, Yasuaki ; Watanabe, Kenichiro ; Takahashi, Chiaki
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金沢大学がん研究所<br />Vascular endothelial cells produce considerable amounts of matrix metalloproteinases (MMP), including MMP
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-2, MMP-9, and membrane type 1 (MT1)-MMP. However, little is known about the regulatory mechanisms of these protease activities exhibited during vascular development. A glycosylphosphatidylinositol-anchored glycoprotein, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), has been shown to attenuate MMP-2 maturation by directly interacting with MT1-MMP. Here, we show that an angiogenic factor angiopoietin-1 induces RECK expression in human umbilical vein endothelial cells (HUVEC), and RECK depletion in these cells results in defective vascular tube formation and cellular senescence. We further observed that RECK depletion downregulates β1-integrin activation, which was associated with decreased autophosphorylation of focal adhesion kinase and increased expression of a cyclin-dependent kinase inhibitor p21CIP1. In agreement, significant downregulation of β1-integrin activity was observed in vascular endothelial cells in Reck-/- mouse embryos. In HUVECs, specific inhibition of MMP-2 significantly antagonized the effect of RECK depletion on β1-integrin signaling, cell proliferation, and tube elongation. Furthermore, we observed that hypervascular tumor-derived cell lines can induce high RECK expression in convoluted vascular endothelial cells, and this in turn supports tumor growth. Targeting RECK specifically in tumor-associated vascular endothelial cells resulted in tumor regression. Therefore, we propose that RECK in tumor vascular endothelial cells can be an interesting target of cancer treatment via abortion of tumor angiogenesis. ©2010 AACR.
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