Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation. Reviewed International journal

Kei Ishii, Mito Kanatsu-Shinohara, Shinya Toyokuni, Takashi Shinohara

Development (Cambridge, England) Vol. 139 ( 10 ) page： 1734 - 43 2012.5

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

Fibroblast growth factor 2 (FGF2) and glial cell line-derived neurotrophic factor (GDNF) are required to recapitulate spermatogonial stem cell (SSC) self-renewal in vitro. Although studies have revealed the role of the GDNF signaling pathway in SSCs, little is known about how FGF2 is involved. In the present study, we assessed the role of the FGF2 signaling pathway using a mouse germline stem (GS) cell culture system that allows in vitro expansion of SSCs. Adding GDNF or FGF2 induced phosphorylation of MAPK1/3, and adding the MAP2K1 inhibitor PD0325091 reduced GS cell proliferation and MAPK1/3 phosphorylation. Moreover, GS cells transfected with an activated form of Map2k1 not only upregulated Etv5 and Bcl6b gene expression, but also proliferated in an FGF2-independent manner, suggesting that they act downstream of MAP2K1 signaling to drive SSC self-renewal. Although GS cells transfected with Map2k1, Etv5 or Bcl6b showed normal spermatogonial markers, transplanting GS cells expressing Bcl6b into infertile mouse testes resulted in the formation of a germ cell tumor, suggesting that excessive self-renewal signals causes tumorigenic conversion. These results show that FGF2 depends on MAP2K1 signaling to drive SSC self-renewal via upregulation of the Etv5 and Bcl6b genes.

DOI： 10.1242/dev.076539

In vitro transformation of mouse testis cells by oncogene transfection. Reviewed International journal

Hiroko Morimoto, Jiyoung Lee, Takashi Tanaka, Kei Ishii, Shinya Toyokuni, Mito Kanatsu-Shinohara, Takashi Shinohara

Biology of reproduction Vol. 86 ( 5 ) page： 148, 1 - 11 2012.5

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

Germ cell tumors (GCTs) are unique in that they exhibit diverse biological characteristics and pathological features. Although several in vivo GCT models are available, studies on GCTs are hampered because in vivo development of GCTs is time consuming and prevents a detailed molecular analysis of the transformation process. Here we developed a novel strategy to transform mouse testis cells in vitro. Lentivirus-mediated transfection of dominant negative Trp53, Myc, and activated Hras1 into a CD9-expressing testis cells caused tumorigenic conversion in vitro. Although these cells resembled embryonic stem (ES) cells, they were aneuploid and lacked Nanog expression, which is involved in the maintenance of the undifferentiated state in ES cells. Euploid ES-like cells were produced by transfecting the Yamanaka factors (Pou5f1, Myc, Klf4, and Sox2) into the same cell population. Although these cells expressed Nanog, they were distinct from ES cells in that they expressed CD44, a cancer stem cell antigen. Both treatments induced similar changes in the DNA methylation patterns in differentially methylated regions of imprinted genes. Moreover, despite the differences in their phenotype and karyotype, both cell types similarly produced mixed GCTs on transplantation, which were composed of teratomas, seminomas, and embryonal carcinomas. Thus, in vitro testis cell transformation facilitates an analysis of the GCT formation process, and our results also suggest the close similarity between GCT formation and reprogramming.

DOI： 10.1095/biolreprod.111.095307

Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy

TOYOKUNI Shinya

Vol. 53 ( 4 ) page： 401 - 408 2012.4

Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy International journal

TOYOKUNI Shinya

Vol. 53 ( 4 ) page： 401 - 408 2012.4

Genome-wide assessment of oxidatively generated DNA damage. Reviewed International journal

Shinya Akatsuka, Shinya Toyokuni

Free radical research Vol. 46 ( 4 ) page： 523 - 30 2012.4

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

In the tide of science nouveau after the completion of genome projects of various species, there appeared a movement to understand an organism as a system rather than the sum of cells directed for certain functions. With the advent and spread of microarray techniques, systematic and comprehensive genome-wide approaches have become reasonably possible and more required on the investigation of DNA damage and the subsequent repair. The immunoprecipitation-based technique combined with high-density microarrays or next-generation sequencing is one of the promising methods to provide access to such novel research strategies. Oxygen is necessary for most of the life on earth for electron transport. However, reactive oxygen species are inevitably generated, giving rise to steady-state levels of DNA damage in the genome, that may cause mutations leading to cancer, ageing and degenerative diseases. Previously, we showed that there are many factors involved in the genomic distribution of oxidatively generated DNA damage including chromosome territory, and proposed this sort of research area as oxygenomics. Recently, RNA is also recognized as a target of this kind of modification.

DOI： 10.3109/10715762.2011.633212

[Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy].

Toyokuni S

[Rinsho ketsueki] The Japanese journal of clinical hematology Vol. 53 ( 4 ) page： 401 - 8 2012.4

[Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy].

Toyokuni S

[Rinsho ketsueki] The Japanese journal of clinical hematology Vol. 53 ( 4 ) page： 401 - 8 2012.4

Age- and sun exposure-dependent differences in 8-hydroxy-2 '-deoxyguanosine and N epsilon-(carboxymethyl)lysine in human epidermis Reviewed International journal

Akira Kawada, Akira Date, Shinya Toyokuni

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Vol. 66 ( 4 ) page： AB174 - AB174 2012.4

[Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy]. Reviewed International journal

Toyokuni S.

[Rinshō ketsueki] The Japanese journal of clinical hematology Vol. 53 ( 4 ) page： 401 - 408 2012.4

多層カーボンナノチューブの直径と剛性は、中皮細胞傷害と中皮腫形成に重要な因子である

永井裕崇, 岡崎泰昌, 周珊瑚, 三澤伸明, 山下依子, 赤塚慎也, 石原敏和, 山下享子, 吉川豊, 安井裕之, 蒋麗, 高橋隆, 市原学, 宮田耕充, 篠原久典, 豊國伸哉

日本病理学会会誌 Vol. 101 ( 1 ) page： 280 - 280 2012.3

Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary Reviewed International journal

Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

LABORATORY INVESTIGATION Vol. 92 page： 302A - 302A 2012.2

Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary Reviewed International journal

Y. Yamashita, S. Akatsuka, Y. Yatabe, S. Toyokuni

MODERN PATHOLOGY Vol. 25 page： 302A - 302A 2012.2

FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b genes through MAP2K1 activation. Reviewed

Ishii K, Kanatsu-Shinohara M, Toyokuni S and Shinohara T.

Development Vol. 139 page： 1734-1743 2012

Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. Reviewed

Nagai H and Toyokuni S.

Cancer Sci Vol. 103 page： 1378-1390 2012

The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. Reviewed

Kobayashi H, Yamashita Y, Iwase A, Yoshikawa Y, Yasui H, Kawai Y, Uchida K, Uno N, Akatsuka S, Takahashi T, Kikkawa F, Toyokuni S.

Fertil Steril Vol. 98 page： 415-422 2012

Mitochondria and free radical studies on health, disease and pollusion (editorial). Invited

Majima HJ and Toyokuni S.

Free Radic Res Vol. 46 page： 925-926 2012

Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. Invited Reviewed

Kubo Y, Takenaka H, Nagai H and Toyokuni S.

J Clin Biochem Nutr Vol. 51 page： 221-226 2012

The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. Reviewed

Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K, Usami N, Shames DS, Kondo M, Gazdar AF, Minna JD and Hasegawa Y.

INt J Cancer Vol. 131 page： 2820-2831 2012

YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes. Reviewed

Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, Akatsuka S, Toyokuni S and Sekido Y.

Oncogene Vol. 31 page： 5117-5122 2012

Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothalioma cells. Reviewed

Horio M, Sato M, Takayama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD and Hasegawa Y.

Ann Surg Oncol Vol. 19 ( Suppl 3 ) page： 634-645 2012

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Papers - TOYOKUNI Shinya