Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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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 International journal Open Access

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 - 508 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 International journal

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

ONCOGENE Vol. 26 ( 48 ) page： 6937 - 47 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 International journal

Shinya Toyokuni, Shinya Akatsuka

PATHOLOGY INTERNATIONAL Vol. 57 ( 8 ) page： 461 - 73 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 Reviewed International journal

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 International journal

Toyokuni, S, Dutta, KK, 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 Reviewed International coauthorship International journal

Lee, WH, 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 International journal Open Access

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 - 9 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

Adenovirus-mediated gene delivery into mouse spermatogonial stem cells Reviewed International journal Open Access

Masanori Takehashi, Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shinya Toyokuni, Atsuo Ogura, Takashi Shinohara

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 104 ( 8 ) page： 2596 - 601 2007.2

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Spermatogonial stem cells represent a self-renewing population of spermatogonia, and continuous division of these cells supports spermatogenesis throughout the life of adult male animals. Previous attempts to introduce adenovirus vectors into spermatogenic cells, including spermatogonial stem cells, have failed to yield evidence of infection, suggesting that male germ cells may be resistant to adenovirus infection. In this study we show the feasibility of transducing spermatogonial stem cells by adenovirus vectors. When testis cells from ROSA26 Cre reporter mice were incubated in vitro with a Cre-expressing adenovirus vector, Cre-mediated recombination occurred at an efficiency of 49-76%, and the infected spermatogonial stem cells could reinitiate spermatogenesis after transplantation into seminiferous tubules of infertile recipient testes. No evidence of germ-line integration of adenovirus vector could be found in offspring from infected stem cells that underwent Cre-mediated recombination, which suggests that the adenovirus vector infected the cells but did not stably integrate into the germ line. Nevertheless, these results suggest that adenovirus may inadvertently integrate into the patient's germ line and indicate that there is no barrier to adenovirus infection in spermatogonial stem cells.

DOI： 10.1073/pnas.0609282104

Adult pancreatic islets require differential pax6 gene dosage Reviewed International journal Open Access

Akihiro Hamasaki, Yuichiro Yamada, Takeshi Kurose, Nobuhiro Ban, Kazuaki Nagashima, Akira Takahashi, Shimpei Fujimoto, Dai Shimono, Michio Fujiwara, Shinya Toyokuni, Yutaka Seino, Nobuya Inagaki

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Vol. 353 ( 1 ) page： 40 - 6 2007.2

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

Pax6, a paired homeodomain transcription factor, plays crucial roles in morphogenesis of eye, central nervous system, and pancreatic islets. Recently, heterozygosity for pax6 mutation has been reported in some individuals with glucose intolerance and aniridia. To investigate the role of pax6 for pancreatic islet function, we examined the pancreatic phenotype of small eye rat strain (rSey(2)) with a point mutation in the pax6 locus resulting in truncated PAX6 proteins. Analyses of the insulin secretory profile of heterozygous rSey(2)/+ revealed that insulin secretion is significantly increased in response to membrane-depolarizing stimuli such as arginine, tolbutamide, and KCl. The processes of insulin granule exocytosis were suggested to be enhanced in rSey(2)/+. On the other hand, pancreatic insulin and glucagon content and islet architecture in rSey(2)/+ showed no significant differences compared to wild-type. These findings indicate differential requirements for pax6 gene dosage in displaying function and maintaining architecture of adult pancreatic islets. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2006.11.105

Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes Reviewed International journal

Masaaki Okuno, Kohtaro Minami, Akinori Okumachi, Kazumasa Miyawaki, Norihide Yokoi, Shinya Toyokuni, Susumu Seino

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Vol. 292 ( 1 ) page： E158 - E165 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

We recently found that pancreatic acinar cells isolated from normal adult mouse can transdifferentiate into insulin-secreting cells in vitro. Using two different animal models of type 1 diabetes, we show here that insulin- secreting cells can also be generated from pancreatic acinar cells of rodents in the diabetic state with absolute insulin deficiency. When pancreatic acinar cells of streptozotocin-treated mice were cultured in suspension in the presence of epidermal growth factor and nicotinamide under low-serum condition, expressions of insulin genes gradually increased. In addition, expressions of other pancreatic hormones, including glucagon, somatostatin, and pancreatic polypeptide, were also induced. Analysis by the Cre/loxP-based direct cell lineage tracing system revealed that these newly made cells originated from amylase-expressing pancreatic acinar cells. Insulin secretion from the newly made cells was significantly stimulated by high glucose and other secretagogues. In addition, insulin- secreting cells were generated from pancreatic acinar cells of Komeda diabetes-prone rats, another animal model of type 1 diabetes. The present study demonstrates that insulin- secreting cells can be generated by transdifferentiation from pancreatic acinar cells of rodents in the diabetic state and further suggests that pancreatic acinar cells represent a potential source of autologous transplantable insulin- secreting cells for treatment of type 1 diabetes.

DOI： 10.1152/ajpendo.00180.2006

Leukemia inhibitory factor enhances formation of germ cell colonies in neonatal mouse testis culture International journal Open Access

Mito Kanatsu-Shinohara, Kimiko Inoue, Narumi Ogonuki, Hiromi Miki, Shosei Yoshida, Shinya Toyokuni, Jiyoung Lee, Atsuo Ogura, Takashi Shinohara

BIOLOGY OF REPRODUCTION Vol. 76 ( 1 ) page： 55 - 62 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SOC STUDY REPRODUCTION

Spermatogonial stem cells continuously divide in the testis to support spermatogenesis throughout the life of adult male animals. Although very few spermatogonial stem cells are present in vivo, we recently succeeded in expanding these cells in vitro. Germ cells from postnatal testes were able to proliferate in the presence of several types of cytokines, and they formed uniquely shaped colonies of spermatogonia (germline stem or GS cells). These cells reinitiated normal spermatogenesis when transplanted into seminiferous tubules. However, much remains unknown about the contributions of cytokines to successful stem cell culture. In the present study, we examined the role of leukemia inhibitory factor (LIF) in GS cell culture. We found that the addition of LIF to newborn testis cell culture enhances the formation of germ cell colonies. Ciliary neurotrophic factor, but not oncostatin M, had the same effect, although they both bind to the IL-6ST (gp130) receptor. On the other hand, GS cells could be established from pup or adult testes in the absence of LIF. No phenotypic or functional difference was found between GS cells established from different stages, and normal offspring were born from pup-derived GS cells that had been maintained in the absence of LIF, indicating that LIF per se is not involved in the self-renewal of GS cells. These results demonstrate that LIF is useful in the initiation of GS cell culture and suggest that LIF or a related cytokine is involved in the maturation of gonocytes into spermatogonia.

DOI： 10.1095/biolreprod.106.055863

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

Liu YT, Shang DH, Akatsuka S, Ohara H, Dutta KK, Mizushima K, Naito Y, Yoshikawa T, Izumiya M, Abe K, Nakagama H, Noguchi N and Toyokuni S.

Am. J. Pathol. Vol. 171 page： 1978-1988 2007

Visualization and characterization of UVB-induced reactive oxygen species in a human skin equivalent model. Reviewed

Hakozaki T, Date A, Yoshii T, Toyokuni S, Yasui H and Sakurai H.

J. Dermatol. Res. Vol. 300 (Supplement 1) page： S51-56 2007

Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. Reviewed

Okuno M, Minami K, Okumachi A, Miyawaki K, Yokoi N, Toyokuni S, Seino S.

Am. J. Physiol. Endocrinol. Metab. Vol. 292 page： E158-165 2007

Oxidative stress is related to formation of Antoni B pattern and eosinophilic hyaline droplets in schwannoma. Reviewed

Yokoo H, Oishi T, Isoda, K, Nakazato Y and Toyokuni S.

Neuropathology Vol. 27 page： 237-244 2007

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Papers - TOYOKUNI Shinya