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Search Results: 1 - 10 of 183 matches for " Tomohisa Horibe "
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The Chop Gene Contains an Element for the Positive Regulation of the Mitochondrial Unfolded Protein Response
Tomohisa Horibe, Nicholas J. Hoogenraad
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000835
Abstract: We have previously reported on the discovery of a mitochondrial specific unfolded protein response (mtUPR) in mammalian cells, in which the accumulation of unfolded protein within the mitochondrial matrix results in the transcriptional activation of nuclear genes encoding mitochondrial stress proteins such as chaperonin 60, chaperonin 10, mtDnaJ, and ClpP, but not those encoding stress proteins of the endoplasmic reticulum (ER) or the cytosol. Analysis of the chaperonin 60/10 bidirectional promoter showed that the CHOP element was required for the mtUPR and that the transcription of the chop gene is activated by mtUPR. In order to investigate the role of CHOP in the mtUPR, we carried out a deletion analysis of the chop promoter. This revealed that the transcriptional activation of the chop gene by mtUPR is through an AP-1 (activator protein-1) element. This site lies alongside an ERSE element through which chop transcription is activated in response to the ER stress response (erUPR). Thus CHOP can be induced separately in response to 2 different stress response pathways. We also discuss the potential signal pathway between mitochondria and the nucleus for the mtUPR.
Discovery of Genes Activated by the Mitochondrial Unfolded Protein Response (mtUPR) and Cognate Promoter Elements
Jonathan E. Aldridge, Tomohisa Horibe, Nicholas J. Hoogenraad
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000874
Abstract: In an accompanying paper, we show that the mitochondrial Unfolded Protein Response or mtUPR is initiated by the activation of transcription of chop through an AP-1 element in the chop promoter. Further, we show that the c/ebpβ gene is similarly activated and CHOP and C/EBPβ subsequently hetero-dimerise to activate transcription of mtUPR responsive genes. Here, we report the discovery of six additional mtUPR responsive genes. We found that these genes encoding mitochondrial proteases YME1L1 and MPPβ, import component Tim17A and enzymes NDUFB2, endonuclease G and thioredoxin 2, all contain a CHOP element in their promoters. In contrast, genes encoding mitochondrial proteins Afg3L2, Paraplegin, Lon and SAM 50, which do not have a CHOP element, were not up-regulated. Conversely, genes with CHOP elements encoding cytosolic proteins were not induced by the accumulation of unfolded proteins in mitochondria. These results indicate that mtUPR responsive genes appear to share a requirement for a CHOP element, but that this is not sufficient for the regulation of the mtUPR. A more detailed analysis of promoters of mtUPR responsive genes revealed at least two additional highly conserved, putative regulatory sites either side of the CHOP element, one a motif of 12 bp which lies 14 bp upstream of the CHOP site and another 9 bp element, 2 bp downstream of the CHOP site. Both of these additional elements are conserved in the promoters of 9 of the ten mtUPR responsive genes we have identified so far, the exception being the Cpn60/10 bidirectional promoter. Mutation of each of these elements substantially reduced the mtUPR responsiveness of the promoters suggesting that these elements coordinately regulate mtUPR.
A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells
Megumi Kawamoto, Tomohisa Horibe, Masayuki Kohno, Koji Kawakami
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-359
Abstract: In vitro: We assessed the cytotoxicity of TfR-lytic hybrid peptide for 12 cancer and 2 normal cell lines. The specificity for TfR is demonstrated by competitive assay using TfR antibody and siRNA. In addition, we performed analysis of confocal fluorescence microscopy and apoptosis assay by Annexin-V binding, caspase activity, and JC-1 staining to assess the change in mitochondria membrane potential. In vivo: TfR-lytic was administered intravenously in an athymic mice model with MDA-MB-231 cells. After three weeks tumor sections were histologically analyzed.The TfR-lytic hybrid peptide showed cytotoxic activity in 12 cancer cell lines, with IC50 values as low as 4.0-9.3 μM. Normal cells were less sensitive to this molecule, with IC50 values > 50 μM. Competition assay using TfR antibody and knockdown of this receptor by siRNA confirmed the specificity of the TfR-lytic hybrid peptide. In addition, it was revealed that this molecule can disintegrate the cell membrane of T47D cancer cells just in 10 min, to effectively kill these cells and induce approximately 80% apoptotic cell death but not in normal cells. The intravenous administration of TfR-lytic peptide in the athymic mice model significantly inhibited tumor progression.TfR-lytic peptide might provide a potent and selective anticancer therapy for patients.The transferrin receptor (TfR) is a cell-membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth [1]. Iron is a required cofactor of heme and nonheme proteins involved in a variety of cellular processes including metabolism and DNA synthesis [2,3]. Therefore, various studies have shown elevated levels of TfR expression on cancer cells when compared with their normal counterparts [4-13]. Bladder-transitional cell carcinomas, breast cancer, glioma, lung adenocarcinoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma also showed increased TfR expression that correlated with tumor grade and stage or prognosi
Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent
Tomohisa Horibe, Masayuki Kohno, Mari Haramoto, Koji Ohara, Koji Kawakami
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-8
Abstract: We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.Heat-shock protein 90 (Hsp90) is a molecular chaperone [1] that participates in the quality control of protein folding. The mechanism of action of Hsp90 includes sequential ATPase cycles and the stepwise recruitment of cochaperones, including Hsp70, CDC37, p60/Hsp-organizing protein (Hop), and p23 [2,3]. In particular, Hsp90 and Hsp70 interact with numerous cofactors containing so-called tetratricopeptide repeat (TPR) domains. TPR domains are composed of loosely conserved 34-amino acid sequence motifs that are repeated between one and 16 times per domain. Originally identified in components of the anaphase-promoting complex [4,5], TPR domains are now known to mediate specific protein interactions in numerous cellular contexts [6-8]. Moreover, apart from serving mere anchoring functions, TPR domains of the chaperone cofactors Hip and p60/Hop also are able to regulate the ATPase activities of Hsp70 and Hsp90, respectively [9,10]. Each 34-amino acid motif forms a pair of antiparallel α-helices. These motifs are arranged in a tandem array into a superhelical structure that encloses a central groove. The TPR-domain-containing cofactors of the Hsp70/Hsp
Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells
Horibe Tomohisa,Torisawa Aya,Kohno Masayuki,Kawakami Koji
Molecular Cancer , 2012, DOI: 10.1186/1476-4598-11-59
Abstract: Background Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo. Results In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition. Conclusion These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy
Kahori Seto,Junichi Shoda,Tomohisa Horibe,Eiji Warabi,Masayuki Kohno,Toru Yanagawa,Hiroki Bukawa,Yasuni Nakanuma,Koji Kawakami
International Journal of Hepatology , 2014, DOI: 10.1155/2014/584650
Abstract: It is known that the interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rα and cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5?μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC. 1. Introduction Biliary tract cancer such as gallbladder cancer and extrahepatic bile duct cancer as well as intrahepatic bile duct cancer (one of the primary liver cancers) is likely to undergo metastasis to the peritoneum (peritoneal dissemination) or the liver at early stages and is often resistant to conventional chemotherapy and radiotherapy. These cancers have been thus viewed as intractable cancers unlikely to be cured completely. In Japan, the incidence of biliary tract cancer and intrahepatic bile duct cancer is about 10 out of every 100,000 people [1]. As for intrahepatic bile duct cancer, both the incidence and death rate have been rising in Japan in recent years, resembling the trend observed in western countries [2, 3]. In Japan, gemcitabine and S-1 have recently begun to be used for anticancer chemotherapy, and these drugs are expected to prolong the survival period of patients as compared to existing anticancer drugs [4]. However, because of frequent adverse events of the hematological system arising from these drugs and because of compromised hepatic function often noted in patients with intrahepatic bile duct cancer due to accompanying liver cirrhosis and in those with extrahepatic bile duct cancer or gallbladder cancer due to accompanying obstructive cholestasis, treatment with these drugs has to be discontinued or stopped. To improve the outcome of treatment of these cancers, it is very
Radioisotopic perfusional assessment of blood circulation changes in skin under progressive expansion: experimental model with rabbits
Horibe, Edith Kawano;Horibe, Kose;
Acta Cirurgica Brasileira , 2004, DOI: 10.1590/S0102-86502004000700015
Abstract: the purpose of this experimental model with rabbits is investigating the variation of blood flow in the expanded skin versus expansion time. new zealand breed rabbits are used. two groups are studied: f-1 receiving expanders on the right tight and f-2 receiving expanders bilateraly. progressively, five expansions are performed. the first radioiosotopic perfusional evaluation is performed just after the surgery and the following evaluation are performed at the second, sixth, thirteenth, twentieth and twenty-seventh post-surgical days. as radiotracer, technetium 99m are used in the chemical form of sodium pertechnetate. scintillographic images are obtained by cgr scintillation camera. the quantitative analysis is done by calculation of the reperfusion rate.
Rikkunshito and Ghrelin
Tomohisa Hattori
International Journal of Peptides , 2010, DOI: 10.1155/2010/283549
Abstract: Rikkunshito is a popular Japanese traditional medicine that is prescribed in Japan to treat various gastrointestinal tract disorders. In a double-blind controlled study, rikkunshito significantly ameliorated dysmotility-like dyspepsia and brought about a generalized improvement in upper gastric symptoms such as nausea and anorexia when compared with a control group. Several studies in rats have shown enhanced gastric emptying and a protective effect on gastric mucosa injury with rikkunshito administration. In addition, rikkunshito in combination with an anti-emetic drug is effective against anorexia and vomiting that occur as adverse reactions to chemotherapy in patients with advanced breast cancer. However, the mechanism by which rikkunshito alleviates gastrointestinal disorders induced by anticancer agents remains unclear. It has recently been shown that rikkunshito ameliorates cisplatin-induced anorexia by mediating an increase in the circulating ghrelin concentration. Moreover, Fujitsuka et al. found that decreased contractions of the antrum and duodenum in rats treated with a selective serotonin reuptake inhibitor were reversed by rikkunshito via enhancement of the circulating ghrelin concentration. These findings show that rikkunshito may be useful for treatment of anorexia and may provide a new strategy for improvement of upper gastrointestinal dysfunction. Rikkunshito is one of the few traditional Japanese medicines for which a double-blind study has been conducted. This trial was performed in patients with dysmotility-like dyspepsia [1, 2] based on a report that rikkunshito showed efficacy against non-ulcer dyspepsia, which is an old diagnostic classification. In a subsequent comparative clinical study, rikkunshito was found to be more effective than cisapride against undefined gastrointestinal complaints such as chronic gastritis [3]. Rikkunshito is prepared by compounding eight herbal medicines listed in the Japanese Pharmacopoeia: Atractylodis Lanceae Rhizoma, Ginseng Radix, Pinelliae Tuber, Hoelen, Zizyphi Fructus, Aurantii Nobilis Pericarpium, Glycyrrhizae Radix and Zingiberis Rhizoma. It has recently been shown that oral administration of rikkunshito stimulates secretion of the orexigenic peptide, ghrelin, from the stomach [4, 5]. In this section, the effects of rikkunshito are introduced, with main focus on the action of rikkunshito as an enhancer of ghrelin secretion. Anorexia is commonly seen in gastrointestinal diseases, although it is not a specific symptom. Anorexia is particularly common in chronic gastritis and gastric cancer but
Relationship between various supersymmetric lattice models
Tomohisa Takimi
Physics , 2007, DOI: 10.1088/1126-6708/2007/07/010
Abstract: We comment on the relationships between several supersymmetric lattice models; the ``orbifold lattice theory'' by Cohen-Kaplan-Katz-Unsal (CKKU), lattice regularization of the topological field theory by Sugino and the ``geometrical approach'' by Catterall. We point out that these three models have close relationships; the N =(2,2) model by Catterall [Catterall] and the two-dimensional N = (2,2) lattice theory being similar to Sugino's construction [Sugino] can be derived by appropriate truncation of fields in the two-dimensional N = (4,4) orbifold lattice theory by CKKU [Cohen et al]. Catterall's N = (2,2) description possesses extra degrees of freedom compared to the target N = (2,2) theory. If we remove those extra degrees of freedom in a way keeping supersymmetry on the lattice, Catterall's description reduces to a model of the Sugino type.
An anisotropic hybrid non-perturbative formulation for 4D N = 2 supersymmetric Yang-Mills theories
Tomohisa Takimi
Physics , 2012, DOI: 10.1007/JHEP08(2012)069
Abstract: We provide a simple non-perturbative formulation for non-commutative four-dimensional N = 2 supersymmetric Yang-Mills theories. The formulation is constructed by a combination of deconstruction (orbifold projection), momentum cut-off and matrix model techniques. We also propose a moduli fixing term that preserves lattice supersymmetry on the deconstruction formulation. Although the analogous formulation for four-dimensional N = 2 supersymmetric Yang-Mills theories is proposed also in Nucl.Phys.B857(2012), our action is simpler and better suited for computer simulations. Moreover, not only for the non-commutative theories, our formulation has a potential to be a non-perturbative tool also for the commutative four-dimensional N = 2 supersymmetric Yang-Mills theories.
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