研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation. 査読有り国際誌

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

Development (Cambridge, England) 139 巻 ( 10 ) 頁： 1734 - 43 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Development

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. © 2012. Published by The Company of Biologists Ltd.

DOI： 10.1242/dev.076539

In vitro transformation of mouse testis cells by oncogene transfection. 査読有り国際誌

Morimoto H, Lee J, Tanaka T, Ishii K, Toyokuni S, Kanatsu-Shinohara M, Shinohara T

Biology of reproduction 86 巻 ( 5 ) 頁： 148, 1 - 11 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biology of 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. © 2012 by the Society for the Study of Reproduction, Inc.

DOI： 10.1095/biolreprod.111.095307

過剰鉄と活性酸素を介した発がん機構と予防・治療への展開

豊國伸哉

臨床血液 53 巻 ( 4 ) 頁： 401 - 408 2012年4月

過剰鉄と活性酸素を介した発がん機構と予防・治療への展開国際誌

豊國伸哉

臨床血液 53 巻 ( 4 ) 頁： 401 - 408 2012年4月

Genome-wide assessment of oxidatively generated DNA damage. 査読有り国際誌

Akatsuka S, Toyokuni S

Free radical research 46 巻 ( 4 ) 頁： 523 - 30 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

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. © 2012 Informa UK, Ltd.

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 53 巻 ( 4 ) 頁： 401 - 8 2012年4月

[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 53 巻 ( 4 ) 頁： 401 - 8 2012年4月

Age- and sun exposure-dependent differences in 8-hydroxy-2′-deoxyguanosine and Nε-(carboxymethyl)lysine in human epidermis 査読有り国際誌

Kawada, A; Date, A; Toyokuni, S

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 66 巻 ( 4 ) 頁： AB174 - AB174 2012年4月

[Carcinogenic mechanisms through excess iron and reactive oxygen species and its application to cancer prevention and therapy]. 査読有り国際誌

Toyokuni S.

[Rinshō ketsueki] The Japanese journal of clinical hematology 53 巻 ( 4 ) 頁： 401 - 408 2012年4月

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 101 巻 ( 1 ) 頁： 280 - 280 2012年3月

Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary 査読有り国際誌

Yamashita, Y; Akatsuka, S; Yatabe, Y; Toyokuni, S

LABORATORY INVESTIGATION 92 巻頁： 302A - 302A 2012年2月

Array CGH Analysis Reveals Amplification of Met and AKT2 in Clear Cell Carcinoma of the Ovary 査読有り国際誌

Yamashita, Y; Akatsuka, S; Yatabe, Y; Toyokuni, S

MODERN PATHOLOGY 25 巻頁： 302A - 302A 2012年2月

The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis. 査読有り

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 98 巻頁： 415-422 2012年

Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis. 査読有り

Nagai H and Toyokuni S.

Cancer Sci 103 巻頁： 1378-1390 2012年

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

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

Development 139 巻頁： 1734-1743 2012年

Bovine lactoferrin ameliorates ferric nitrilotriacetate-induced renal oxidative damage in rats. 査読有り

Okazaki Y, Kono H, Kuriki R, Funahashi S, Fushimi S, Iqbal M, Okada S and Toyokuni S.

J Clin Biochem Nutr 51 巻頁： 84-90 2012年

Mitochondria and free radical studies on health, disease and pollusion (editorial). 招待有り

Majima HJ and Toyokuni S.

Free Radic Res 46 巻頁： 925-926 2012年

Distinct affinity of nuclear proteins to the surface of chrysotile and crocidolite. 招待有り査読有り

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

J Clin Biochem Nutr 51 巻頁： 221-226 2012年

The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. 査読有り

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 131 巻頁： 2820-2831 2012年

YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes. 査読有り

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

Oncogene 31 巻頁： 5117-5122 2012年

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