研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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

Toyokuni, S, Dutta, KK, Akatsuka, S

AMERICAN JOURNAL OF HEMATOLOGY 82 巻 ( 6 ) 頁： 512 - 512 2007年6月

Analysis of genes associated with karyomegalic cells in rat kidney after ferric nitilotriacetate treatment 査読有り国際共著国際誌

Lee, WH, Toyokuni, S

AMERICAN JOURNAL OF HEMATOLOGY 82 巻 ( 6 ) 頁： 602 - 602 2007年6月

Akt mediates self-renewal division of mouse spermatogonial stem cells. 査読有り国際誌 Open Access

Lee J, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Kimura T, Nakano T, Ogura A, Shinohara T

Development (Cambridge, England) 134 巻 ( 10 ) 頁： 1853 - 9 2007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

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 (P13K)-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 P13K 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 P13K-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. 査読有り国際誌 Open Access

Takehashi M, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Ogura A, Shinohara T

Proceedings of the National Academy of Sciences of the United States of America 104 巻 ( 8 ) 頁： 2596 - 601 2007年2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：Proceedings of the National Academy of Sciences of the United States of America

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. © 2007 by The National Academy of Sciences of the USA.

DOI： 10.1073/pnas.0609282104

Adult pancreatic islets require differential pax6 gene dosage. 査読有り国際誌 Open Access

Hamasaki A, Yamada Y, Kurose T, Ban N, Nagashima K, Takahashi A, Fujimoto S, Shimono D, Fujiwara M, Toyokuni S, Seino Y, Inagaki N

Biochemical and biophysical research communications 353 巻 ( 1 ) 頁： 40 - 6 2007年2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：Biochemical and Biophysical Research Communications

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 (rSey2) with a point mutation in the pax6 locus resulting in truncated PAX6 proteins. Analyses of the insulin secretory profile of heterozygous rSey2/+ 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 rSey2/+. On the other hand, pancreatic insulin and glucagon content and islet architecture in rSey2/+ 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. © 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 査読有り国際誌

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

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 292 巻 ( 1 ) 頁： E158 - E165 2007年1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：American Journal of Physiology - Endocrinology and Metabolism

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 diabetesprone 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. Copyright © 2007 the American Physiological Society.

DOI： 10.1152/ajpendo.00180.2006

Leukemia inhibitory factor enhances formation of germ cell colonies in neonatal mouse testis culture. 国際誌 Open Access

Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Yoshida S, Toyokuni S, Lee J, Ogura A, Shinohara T

Biology of reproduction 76 巻 ( 1 ) 頁： 55 - 62 2007年1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

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 CS 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. © 2007 by the Society for the Study of Reproduction, Inc.

DOI： 10.1095/biolreprod.106.055863

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

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. 171 巻頁： 1978-1988 2007年

Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes. 査読有り

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

Am. J. Physiol. Endocrinol. Metab. 292 巻頁： E158-165 2007年

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

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

Neuropathology 27 巻頁： 237-244 2007年

Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension. 査読有り

Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T.

J. Mol. Cell. Cardiol. 41 巻頁： 989-997 2007年

Leukemia inhibitory factor enhances formation of germ cell colonies in neonatal mouse testis culture.

Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Yoshida S, Toyokuni S, Lee J, Ogura A and Shinohara T.

Biol. Reprod. 76 巻頁： 55-62 2007年

Adult pancreatic islets require differential pax6 gene dosage. 査読有り

Hamasaki A, Yamada Y, Kurose T, Ban N, Nagashima K, Takahashi A, Fujimoto S, Shimono D, Fujiwara M, Toyokuni S, Seino Y and Inagaki N.

Biochem. Biophys. Res. Commun. 353 巻頁： 40-46 2007年

Adenovirus-mediated gene delivery into mouse spermatogonial stem cells. 査読有り

Takehashi M, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Ogura A, and Shinohara T.

Proc. Natl. Acad. Sci. USA 104 巻頁： 2596-2601 2007年

Pathological investigation of oxidative stress in the post-genomic era. 招待有り査読有り

Toyokuni S and Akatsuka S.

Pathol. Int. 57 巻頁： 461-473 2007年

Overexpressin of a transcription factor LYL-1 induces T- and B-cell lymphoma in mice. 査読有り

Zhong Y, Li J, Hiai H, Toyokuni S* and Yamada Y* (*corresponding author).

Oncogene 26 巻頁： 6937-6947 2007年

ARMET is a soluble ER protein induced by the unfolded protein response via ERSE-II element. 査読有り

Mizobuchi N, Hoseki J, Kubota H, Toyokuni S, Nozaki J, Naitoh M, Koizumi A and Nagata K.

Cell Struct. Funct. 32 巻頁： 41-50 2007年

Akt mediates self-renewal division of mouse spermatogonial stem cells. 査読有り

Lee J, Kanatsu-Shinohara M, Inoue K, Ogonuki N, Miki H, Toyokuni S, Kimura T, Nakano T, Ogura A and Shinohara T.

Development 134 巻頁： 1853-1859 2007年

Association of microRNA-34a overexpression with proliferation is cell type-dependent. 査読有り

Dutta KK, Zhong Y, Liu YT, Yamada T, Akatsuka S, Hu Q, Yoshihara M, Ohara H, Takehashi M, Shinohara T, Masutani H, Onuki J and Toyokuni S.

Cancer Sci. 98 巻頁： 1845-1852 2007年

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. 査読有り

Miyagawa-Hayashino A, Tsuruyama T, Egawa H, Haga H, Sakashita H, Okuno T, Toyokuni S, Tamaki K, Yamabe H, Manabe T and Uemoto S.

Am J. Pathol. 171 巻頁： 1499-1508 2007年

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