Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma. Reviewed

Zhong Y, Onuki J, Yamasaki T. Ogawa O, Akatsuka S and Toyokuni S.

Carcinogenesis page： in press 2008

A high-throughput reporter gene assay to prove the ability of natural compounds to modulate glutathione peroxidase, superoxide dismutase and catalase gene promoters in V79 cells. Reviewed International journal

Kristina Ullmann, Anne Maria Wiencierz, Carsten Müller, Rene Thierbach, Andreas Steege, Shinya Toyokuni, Pablo Steinberg

Free radical research Vol. 42 ( 8 ) page： 746 - 753 2008

Language：English Publishing type：Research paper (scientific journal) Publisher：INFORMA HEALTHCARE

The aim of the study was to establish a 96-well microtiter plate-based reporter gene assay to test the influence of natural compounds on the promoter activities of rat catalase, human glutathione peroxidase and human superoxide dismutase expressed in V79 cells. Luciferase expression vectors with the promoter regions of the genes coding for the three above-mentioned enzymes were constructed and transfected into V79 cells. Thereafter the ability of sodium ascorbate, L-carnitine, catechin, epigallocatechin gallate, genistein, paraquat, quercetin, 12-O-tetradecanoylphorbol-13-acetate and Trolox to enhance the promoter activities was evaluated. Genistein, paraquat and quercetin led to a statistically significant increase in the glutathione peroxidase and superoxide dismutase gene promoter activities. None of the compounds tested enhanced the catalase gene promoter activity. The reporter gene assay described in this report is easy to perform, fast and allows one to test a high number of compounds and different concentrations of a single compound at the same time.

DOI： 10.1080/10715760802337273

Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inihibitor FK228 through AIF translocation. Reviewed

Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe KI, Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Tokuchida J, Nakahata T

Int. J. Cancer Vol. 124 page： 55-67 2008

Molecular mechanisms of oxidative stress-induced carcinogenesis: from epidemiology to oxygenomics. Invited Reviewed

Toyokuni S

IUBMB Life Vol. 60 page： 441-447 - 447 2008

Association of microRNA-34a overexpression with proliferation is cell type-dependent

DUTTA Khokon Kumar, ZHONG Yi, LIU Yu-Ting, YAMADA Takuji, AKATSUKA Shinya, HU Qian, YOSHIHARA Minako, OHARA Hiroki, TAKEHASHI Masanori, SHINOHARA Takashi, MASUTANI Hiroshi, ONUKI Janice, TOYOKUNI Shinya

Cancer Sci. Vol. 98 ( 12 ) page： 1845 - 1852 2007.12

Production of knockout mice by gene targeting in multipotent germline stem cells Reviewed

Masanori Takehashi, Mito Kanatsu-Shinohara, Hiromi Miki, Jiyoung Lee, Yasuhiro Kazuki, Kimiko Inoue, Narumi Ogonuki, Shinya Toyokuni, Mitsuo Oshimura, Atsuo Ogura, Takashi Shinohara

DEVELOPMENTAL BIOLOGY Vol. 312 ( 1 ) page： 344 - 352 2007.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Spermatogonial stein cells can convert into embryonic stem (ES) cell-like multipotent germline stem (mGS) cells in vitro and produce germline chimeras by blastocyst microinjection. Although homologous recombination was previously demonstrated in mGS cells, spermatogenesis was not found in chimeras, suggesting that they are not competent for germline modification. Here we conducted detailed analysis of chimeric animals to determine whether mGS cells retain germline potential after genetic manipulation. Spermatozoa that were deficient in the occludin gene could be recovered from animals that were chimeric with mGS cells that underwent homologous recombination. The phenotypes of the occludin knockout (KO) mice were similar to those reported for KO mice produced using ES cells, and the animals showed growth retardation, gastritis and male infertility. Furthermore, we found that heterozygous mGS cells acquire two copies of the G418-resistant genes and become homozygous for the targeted allele by culturing at high concentrations of G418. Cytogenetic analysis showed that the aneuploid mGS cells observed during genetic manipulation were trisomic for chromosome 8 or 11, which is a common chromosomal abnormality in ES cells. Thus, mGS cells can be used to produce KO animals, and this novel method of germline manipulation may prove useful in diverse mammalian species. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ydbio.2007.09.029

Association of microRNA-34a overexpression with proliferation is cell type-dependent Reviewed

Khokon Kumar Dutta, Yi Zhong, Yu-Ting Liu, Takuji Yamada, Shinya Akatsuka, Qian Hu, Minako Yoshihara, Hiroki Ohara, Masanori Takehashi, Takashi Shinohara, Hiroshi Masutani, Janice Onuki, Shinya Toyokuni

CANCER SCIENCE Vol. 98 ( 12 ) page： 1845 - 1852 2007.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Recently Welch et al. reported that microRNA (miRNA)-34a functions as a potential tumor suppressor in neuroblastoma cells (Oncogene 26: 5017-22, 2007). Here, we conversely show that miRNA-34a supports cell proliferation in rat oxidative stress-induced renal carcinogenesis and is overexpressed in various types of human cancers. While searching for genetically unstable chromosomal areas in rat renal carcinogenesis, we found the miRNA-34 family reciprocally overexpressed in chromosomal areas with frequent allelic loss. By in situ hybridization and reverse transcription-polymerase chain reaction, cerebral neurons and Purkinje cells showed the highest expression of a major type, miRNA-34a, followed by a variety of endocrine cells and proliferating cells including germinal center lymphocytes and mouse embryonic fibroblasts and stem cells. In contrast, normal renal tubules, hepatocytes and myocardial cells showed faint expression. After 3 weeks of ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress, regenerating renal proximal tubular cells showed high miRNA-34a expression. All of the Fe-NTA-induced rat renal carcinomas and an array of human cancers (151 positive cases of 177) showed high expression of miRNA-34a. Furthermore, knockdown of miRNA-34a with small interfering RNA significantly suppressed proliferation not only of renal carcinoma cells but also of HeLa and MCF7 cells. These results indicate that miRNA-34a overexpression, an acquired trait during carcinogenesis, supports cell proliferation in the majority of cancers suggesting an unexpected link in the cellular metabolism between cancer and neuronal and/or endocrine cells, which warrants further investigation.

DOI： 10.1111/j.1349-7006.2007.00619.x

Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway

Liu Yu-Ting, Shang Donghao, Akatsuka Shinya, Ohara Hiroki, Dutta Khokon Kumar, Mizushima Katsura, Naito Yuji, Yoshikawa Toshikazu, Izumiya Masashi, Abe Kouichiro, Nakagama Hitoshi, Noguchi Noriko, Toyokuni Shinya

AMERICAN JOURNAL OF PATHOLOGY Vol. 171 ( 6 ) page： 1978 - 1988 2007.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology

Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase ζ or receptor tyrosine phosphatase β) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16∼552-fold in the RCCs. Network analysis of the expression revealed the involvement of the β-catenin pathway in the RCCs. In the RCCs, dephosphorylated β-catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear β-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating β-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification. Copyright © American Society for Investigative Pathology.

DOI： 10.2353/ajpath.2007.070741

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Scopus

PubMed

Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway Reviewed

Yu-Ting Liu, Donghao Shang, Shinya Akatsuka, Hiroki Ohara, Khokon Kumar Dutta, Katsura Mizushima, Yuji Naito, Toshikazu Yoshikawa, Masashi Izumiya, Kouichiro Abe, Hitoshi Nakagama, Noriko Noguchi, Shinya Toyokuni

AMERICAN JOURNAL OF PATHOLOGY Vol. 171 ( 6 ) page： 1978 - 1988 2007.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase zeta or receptor tyrosine phosphatase beta) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16 similar to 552-fold in the RCCs. Network analysis of the expression revealed the involvement of the beta-catenin pathway in the RCCs. in the RCCs, dephosphorylated beta-catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear beta-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating beta-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification.

DOI： 10.2353/ajpath.2007-070741

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FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL(+) Kupffer cells are indicators of rejection activity in human liver Allografts Reviewed

Aya Miyagawa-Hayashino, Tatsuaki Tsuruyama, Hiroto Egawa, Hironori Haga, Hirorni Sakashita, Tomoko Okuno, Shinya Toyolkuni, Keiji Tamaki, Hirohiko Yamabe, Toshialki Manabe, Shinji Uemoto

AMERICAN JOURNAL OF PATHOLOGY Vol. 171 ( 5 ) page： 1499 - 1508 2007.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Fas-Fas figand (FasL) interaction and apoptosis are important in the mechanism of allograft rejection. However, the interaction between donor and recipient cells, specifically focusing on antigen-presenting cells (APCs), under various conditions is poorly understood in human liver allografts. FasL expression on APCs, its association with apoptosis, and the origin of apoptotic lymphocytes in human liver allografts were assessed by immunohistochemistry and in situ hybridization. We found increased expression of FasL on Kupffer cells (KCs) and endothelium in acute cellular rejection (n = 20) and to lesser extent in chronic rejection (n = 6) and septic cholangitis (n = 5) compared with stable grafts and normal controls. in addition, the graft specificity of infiltrating T cells was confirmed by polymerase chain reaction examination of T-cell receptor-gamma loci. T-cell apoptosis occurred at a higher rate in acute cellular rejection than in chronic rejection or septic cholangitis. The number of apoptotic bodies derived from recipient lymphocytes correlated with the severity of rejection and was reversed by treatment. FasL(+) KCs phagocytosed CD4(+) interferon-gamma(+) T cells, rather than CD4(+) interleukin-4(+) T cells, suggesting a role of KCs in regulating CD4+ T-cell subset differentiation. in conclusion, our data suggest that FasL expression on APCs and phagocytosis of apoptotic T cells by FasL(+) KCs are indicators of rejection activity in human liver allografts.

DOI： 10.2353/ajpath.2007.070027

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice Reviewed

Y. Zhong, L. Jiang, H. Hiai, S. Toyokuni, Y. Yamada

ONCOGENE Vol. 26 ( 48 ) page： 6937 - 6947 2007.10

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

LYL1, a member of the class II basic helix-loop-helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor lot promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavy-chain gene rearrangement analyses. Mammalian two-hybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis.

DOI： 10.1038/sj.onc.1210494

Pathological investigation of oxidative stress in the post-genomic era Invited Reviewed

Shinya Toyokuni, Shinya Akatsuka

PATHOLOGY INTERNATIONAL Vol. 57 ( 8 ) page： 461 - 473 2007.8

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Aerobes, including humans, are consistently exposed to oxidative stress by consuming oxygen. The biological significance of oxidative stress via reactive oxygen and nitrogen species consists of two stages: reversible redox regulation and irreversible oxidative molecular damage, which are sometimes intermingled. During the past decade, many signaling cascades associated with oxidative stress have been discovered. An interaction between Keap1 and the Nrf2 transcription factor is among the most fundamental mechanisms of the defense system against oxidative or similar stress. Furthermore, it became apparent that reactive oxygen species are actively produced through enzymes such as xanthine oxidoreductase and nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidases in non-phagocytic cells as well. The role of alpha-tocopherol solely as an anti-oxidant was also questioned. Now there is a long list of pathological states implicating oxidative stress. At the same time, genome projects on various species have been completed. These efforts convincingly led to a new era of oxidative stress investigation, contributing powerful strategies to select candidate genes or biomolecules. Herein are reviewed recent advances and novel concepts in this field, including oxygenomics. These fruitful results may lead to more accurate and useful pathological diagnosis and more efficient prophylaxis and therapeutic interventions on human diseases.

DOI： 10.1111/j.1440-1827.2007.02127.x

アレイCGH法を用いた酸化ストレス誘発ラット腎癌における染色体変化の解析(Analysis of chromosomal alterations in oxidative stress-induced rat renal carcinomas using array-based CGH)

赤塚慎也, 泉谷昌志, 阿部浩一郎, 劉玉亭, 胡茜, 大原浩貴, 落合雅子, 中釜斉, 豊國伸哉

日本癌学会総会記事 Vol. 66回 page： 343 - 344 2007.8

Oxidative stress is related to the formation of Antoni B patterns and eosinophilic hyaline droplets in schwannomas

YOKOO Hideaki, OISHI Takuma, ISODA Koji, NAKAZATO Yoichi, TOYOKUNI Shinya

Vol. 27 ( 3 ) page： 237 - 244 2007.6

Analysis of genes associated with karyomegalic cells in rat kidney after ferric nitilotriacetate treatment

Lee, WH; Toyokuni, S

AMERICAN JOURNAL OF HEMATOLOGY Vol. 82 ( 6 ) page： 602 - 602 2007.6

Novel approach for elucidation of iron-induced carcinogenesis: Oxygenomics and micro-RNA

Toyokuni, S; Dutta, KK; Akatsuka, S

AMERICAN JOURNAL OF HEMATOLOGY Vol. 82 ( 6 ) page： 512 - 512 2007.6

Oxidative stress is related to the formation of Antoni B patterns and eosinophilic hyaline droplets in schwannomas

Yokoo, H; Oishi, T; Isoda, K; Nakazato, Y; Toyokuni, S

NEUROPATHOLOGY Vol. 27 ( 3 ) page： 237 - 244 2007.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Neuropathology

Schwannomas, particularly of vestibular origin, often accompany degenerative hypocellular areas known as Antoni B patterns; however, the detailed mechanism is uncertain. Eosinophilic hyaline droplets (EHD), the substantial nature of which are autophagic vacuoles, preferentially appear in acoustic schwannomas and distribute around areas of Antoni B. We investigated their common background using schwannomas with (15 cases) or without (10 cases) EHD, and demonstrated that EHD showed selective immunoreactivity with an anti-nitrotyrosine antibody, suggesting the overproduction of nitric oxide in this condition. The expression of inducible nitric oxide synthase was emphasized in infiltrating macrophages around hyalinized vessels. Protein-bound 4-hydroxy 2-nonenal, another oxidative stress marker, was detected in Antoni B tissue, but not in EHD. Antibodies to cleaved caspase-3 and single strand DNA, indicators of apoptosis, did not label tumors cells in Antoni B areas as well as EHD-bearing cells. The morphology and the mitotically static state of EHD-laden cells are phenotypically similar to autophagic cell death; however, autophagy in normal cells is a cell survival strategy against starvation, so the possibility remains that EHD are formed in that context. In either case, schwannomas may show a characteristic autophagic change by an endogenous mechanism. Tumor growth in a narrow intracranial space and resultant ischemia by self-oppression were postulated to be an initial event, because ischemia-reperfusion injury is a major source of reactive oxygen species and ischemia is also a potent trigger of autophagy as well as of tissue degeneration. Moreover, potential roles of chemokines and hemosiderosis are discussed. © 2007 Japanese Society of Neuropathology.

DOI： 10.1111/j.1440-1789.2007.00772.x

Web of Science

Scopus

PubMed

Novel approach for elucidation of iron-induced carcinogenesis: Oxygenomics and micro-RNA

Toyokuni S, Dutta K. K, Akatsuka S

AMERICAN JOURNAL OF HEMATOLOGY Vol. 82 ( 6 ) page： 512 - 512 2007.6

Analysis of genes associated with karyomegalic cells in rat kidney after ferric nitilotriacetate treatment

Lee W. H, Toyokuni S

AMERICAN JOURNAL OF HEMATOLOGY Vol. 82 ( 6 ) page： 602 - 602 2007.6

Akt mediates self-renewal division of mouse spermatogonial stem cells Reviewed

Jiyoung Lee, Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokuni, Tohru Kimura, Toru Nakano, Atsuo Ogura, Takashi Shinohara

DEVELOPMENT Vol. 134 ( 10 ) page： 1853 - 1859 2007.5

Language：English Publishing type：Research paper (scientific journal) Publisher：COMPANY OF BIOLOGISTS LTD

Spermatogonial stem cells have unique properties to self-renew and support spermatogenesis throughout their lifespan. Although glial cell line-derived neurotrophic factor ( GDNF) has recently been identified as a self-renewal factor for spermatogonial stem cells, the molecular mechanism of spermatogonial stem cell self-renewal remains unclear. In the present study, we assessed the role of the phosphoinositide-3 kinase (PI3K)-Akt pathway using a germline stem (GS) cell culture system that allows in vitro expansion of spermatogonial stem cells. Akt was rapidly phosphorylated when GDNF was added to the GS cell culture, and the addition of a chemical inhibitor of PI3K prevented GS cell self-renewal. Furthermore, conditional activation of the myristoylated form of Akt-Mer (myr-Akt-Mer) by 4-hydroxy-tamoxifen induced logarithmic proliferation of GS cells in the absence of GDNF for at least 5 months. The myr-Akt-Mer GS cells expressed spermatogonial markers and retained androgenetic imprinting patterns. In addition, they supported spermatogenesis and generated offspring following spermatogonial transplantation into the testes of infertile recipient mice, indicating that they are functionally normal. These results demonstrate that activation of the PI3K-Akt pathway plays a central role in the self-renewal division of spermatogonial stem cells.

DOI： 10.1242/dev.003004

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Papers - TOYOKUNI Shinya