Nishizawa K.,Kyoto University |
Nishiyama H.,Kyoto University |
Matsui Y.,Kyoto University |
Kobayashi T.,Kyoto University |
And 6 more authors.
Carcinogenesis | Year: 2011
Thioredoxin-interacting protein (TXNIP), which has a tumor-suppressive function, is underexpressed in some human cancers. The function of TXNIP in vivo in carcinogenesis is not fully understood. Here, we show TXNIP to be downregulated in human bladder cancer according to grade and stage and also that loss of TXNIP expression facilitates bladder carcinogenesis using a mouse bladder cancer model. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer was found in 100% of Txnip knockout (KO) mice at week 8 of 0.025% BBN administration but in only 22% of wild-type (WT) mice at the same point. Among growth stimulators, phospho-extracellular signal-regulated kinase (pERK) expression was stronger during bladder carcinogenesis in Txnip-KO mice than in WT mice. We then evaluated TXNIP's effects on ERK activation through various growth stimulators and their receptors. Overexpression of TXNIP in human bladder cancer cells attenuated pERK expression upon stimulation with stromal cell-derived factor-1 (SDF-1) but not with epidermal growth factor or insulin-like growth factor-1. In Txnip-KO mice, immunohistochemical analysis showed enhanced expression of C-X-C chemokine receptor type 4 (CXCR4), the receptor of SDF-1, and of pERK in urothelial cells during BBN-induced bladder carcinogenesis. Finally, subcutaneous injection of CXCR4 antagonist, TF14016, attenuated pERK in urothelial cells and suppressed bladder carcinogenesis. These data indicate that TXNIP negatively regulates bladder carcinogenesis by attenuating SDF-1-CXCR4-induced ERK activation. This signal transduction pathway can be a potent target in preventing or treating bladder cancer. © The Author 2011. Published by Oxford University Press. All rights reserved.
Satsuka A.,Institute for Virus Research |
Satsuka A.,Laboratory of Mammalian Molecular Biology |
Yoshida S.,Institute for Virus Research |
Yoshida S.,Kyoto University |
And 5 more authors.
Cancer Science | Year: 2010
Human papillomaviruses (HPVs) infect the stratified epithelial organ. The infection induces benign tumors, which occasionally progress into malignant tumors. To elucidate the virus-induced tumorigenesis, an understanding of the lifecycle of HPV is crucial. In this report, we developed a new system for the analysis of the HPV lifecycle. The new system consists of a novel HPV replicon and an organotypic " raft" culture, by which the HPV-DNA is maintained stably in normal human keratinocytes for a long period and the viral vegetative replication is reproduced. This system will benefit biochemical and genetic studies on the lifecycle of HPV and tumorigenesis. This system is also valuable in screening for antiviral compounds. We confirmed its usefulness by evaluating the antivirus effect of cytokines. © 2009 Japanese Cancer Association.
Watanabe R.,Institute for Virus Research |
Nakamura H.,The Tazuke Kofukai Medical Research Institute Kitano Hospital |
Masutani H.,Institute for Virus Research |
Yodoi J.,Institute for Virus Research
Pharmacology and Therapeutics | Year: 2010
Thioredoxin 1 (Trx 1) is a 12-kDa protein with redox-active dithiol in the active site -Cys-Gly-Pro-Cys- that is ubiquitously present in the human body. Trx 1 is a defensive protein induced by various stresses and has anti-oxidative, anti-apoptotic and anti-inflammatory effects. The anti-oxidative effect of Trx 1 is mediated by the dithiol-disulfide exchange in the active site. Trx 1 is able to interact with certain molecules, one of which is thioredoxin-binding protein-2 (TBP-2)/Vitamin D3 upregulated protein 1 (VDUP1)/thioredoxin interacting protein (TXNIP). TBP-2 was originally identified as a negative regulator of Trx 1 and acts as a cell growth suppressor and a regulator in lipid/glucose metabolism. Trx 1 and TBP-2 play crucial roles in pathophysiological mechanisms in metabolic disorders, cancer and inflammation. Here we discuss pharmacological aspects of Trx 1 and TBP-2 in these diseases and propose potential therapeutic approaches for intractable oxidative stress-related disorders. © 2010 Elsevier Inc.
Mogami H.,Kyoto University |
Yura S.,Kyoto University |
Yura S.,Japan Science and Technology Agency |
Tatsumi K.,Kyoto University |
And 8 more authors.
Pediatric Research | Year: 2010
Glucose is a major fuel for fetal development. Fetal blood glucose level is mainly dependent on maternal blood glucose concentration, though it is also regulated by fetal insulin level. Thioredoxin binding protein-2 (TBP-2), which is identical to vitamin D3 up-regulated protein (VDUP1) and thioredoxin interacting protein (Txnip), was recently reported to be a key transcriptional factor controlling glucose metabolism. Here, we elucidated the functions of TBP-2 in maintaining blood glucose homeostasis during the fetal period. TBP-2 female mice were mated with TBP-2 male mice; beginning 16.5-d post coitum, pregnant mice were fed or fasted for 24 h. Under conditions of maternal starvation, the blood glucose levels of TBP-2 fetuses were significantly lower than those of TBP-2 fetuses, corresponding to the elevated plasma insulin levels of TBP-2 fetuses compared with those of TBP-2 fetuses. There was no difference between TBP-2 and TBP-2 fetuses in terms of their pancreatic β-cell masses or the expression of placental glucose transporters under conditions of either maternal feeding or fasting. Thus, during maternal fasting, fetal TBP-2 suppresses excessive insulin secretion to maintain the fetus's glucose levels, implying that TBP-2 is a critical molecule in mediating fetal glucose homeostasis depending on nutrient availability. Copyright © 2010 International Pediatric Research Foundation, Inc.
Ohno R.,Kwansei Gakuin University |
Nakayama M.,Kwansei Gakuin University |
Naruse C.,Kanazawa University |
Okashita N.,Kwansei Gakuin University |
And 8 more authors.
Development (Cambridge) | Year: 2013
Germline cells reprogramme extensive epigenetic modifications to ensure the cellular totipotency of subsequent generations and to prevent the accumulation of epimutations. Notably, primordial germ cells (PGCs) erase genome-wide DNA methylation and H3K9 dimethylation marks in a stepwise manner during migration and gonadal periods. In this study, we profiled DNA and histone methylation on transposable elements during PGC development, and examined the role of DNA replication in DNA demethylation in gonadal PGCs. CpGs in short interspersed nuclear elements (SINEs) B1 and B2 were substantially demethylated in migrating PGCs, whereas CpGs in long interspersed nuclear elements (LINEs), such as LINE-1, were resistant to early demethylation. By contrast, CpGs in both LINE-1 and SINEs were rapidly demethylated in gonadal PGCs. Four major modifiers of DNA and histone methylation, Dnmt3a, Dnmt3b, Glp and Uhrf1, were actively repressed at distinct stages of PGC development. DNMT1 was localised at replication foci in nascent PGCs, whereas the efficiency of recruitment of DNMT1 into replication foci was severely impaired in gonadal PGCs. Hairpin bisulphite sequencing analysis showed that strand-specific hemi-methylated CpGs on LINE-1 were predominant in gonadal PGCs. Furthermore, DNA demethylation in SINEs and LINE-1 was impaired in Cbx3-deficient PGCs, indicating abnormalities in G1 to S phase progression. We propose that PGCs employ active and passive mechanisms for efficient and widespread erasure of genomic DNA methylation. © 2013. Published by The Company of Biologists Ltd.
PubMed | Institute for Virus Research
Type: Journal Article | Journal: Microbiology and immunology | Year: 2016
The range of genome-editing tools has recently been expanded. In particular, an RNA-guided genome-editing tool, the clustered regularly interspaced short palindromic repeat (CRISPR)-associated 9 (Cas9) system, has many applications for human diseases. In this study, guide RNA (gRNA) to target gag, pol and a long terminal repeat of HIV-1 was designed and used to generate gRNA-expressing lentiviral vectors. An HIV-1-specific gRNA and Cas9 were stably dually transduced into a highly HIV-1-susceptible human T-cell line and the inhibitory ability of the anti-HIV-1 CRISPR/Cas9 lentiviral vector assessed. Although clear inhibition of the early phase of HIV-1 infection was observed, as evaluated by a VSV-G-pseudotyped HIV-1 reporter system, the anti-HIV-1 potency in multiple rounds of wild type (WT) viral replication was insufficient, either because of generation of resistant viruses or overcoming of the activity of the WT virus. Thus, there are potential difficulties that must be addressed when considering anti-HIV-1 treatment with the CRISPR/Cas9 system alone.
PubMed | Institute for Virus Research and Kagoshima University
Type: Journal Article | Journal: Microbiology and immunology | Year: 2016
In this study, the genome sequence of a new parrot bornavirus-5 (PaBV-5) detected in Eclectus roratus was determined. Phylogenetic analysis showed that the genus Bornavirus is divided into three major clades and that PaBV-5 belongs to clade 2, which contains avian viruses that exhibit infectivity to mammalian cells. Sequence comparisons of the regions known to interact with host factors indicated that the clade 2 avian viruses possess sequences intermediate between the clade 1 mammalian viruses and the clade 3 avian viruses, suggesting that the identified regions might contribute to the differences in virological properties between the three clades.
PubMed | Institute for Virus Research, Kyoto University and University of Wisconsin - Oshkosh
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
Animal genomes contain endogenous viral sequences, such as endogenous retroviruses and retrotransposons. Recently, we and others discovered that nonretroviral viruses also have been endogenized in many vertebrate genomes. Bornaviruses belong to the Mononegavirales and have left endogenous fragments, called endogenous bornavirus-like elements (EBLs), in the genomes of many mammals. The striking features of EBLs are that they contain relatively long ORFs which have high sequence homology to the extant bornavirus proteins. Furthermore, some EBLs derived from bornavirus nucleoprotein (EBLNs) have been shown to be transcribed as mRNA and probably are translated into proteins. These features lead us to speculate that EBLs may function as cellular coopted genes. An EBLN element in the genome of the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), itEBLN, encodes an ORF with 77% amino acid sequence identity to the current bornavirus nucleoprotein. In this study, we cloned itEBLN from the ground squirrel genome and investigated its involvement in Borna disease virus (BDV) replication. Interestingly, itEBLN, but not a human EBLN, colocalized with the viral factory in the nucleus and appeared to affect BDV polymerase activity by being incorporated into the viral ribonucleoprotein. Our data show that, as do certain endogenous retroviruses, itEBLN potentially may inhibit infection by related exogenous viruses in vivo.