研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis 査読有り

S. Akatsuka, T. T. Aung, K. K. Dutta, L. Jiang, Y. Liu, W. Lee, J. Onuki, T. Shirase, Y. Naito, T. Yoshikawa, K. Uchida, S. Toyokuni

FREE RADICAL RESEARCH 40 巻頁： S129 - S129 2006年

Imidapril, an angiotensin-converting enzyme inhibitor, reduces diabetes-induced renal oxidative damage in mice

Naito Y., Uchiyama K., Akagiri S., Aoi W., Hasegawa G., Nakamura N., Kokura S., Yoshida N., Ichikawa H., Toyokuni S., Yoshikawa T.

Journal of Clinical Biochemistry and Nutrition 37 巻 ( 1 ) 頁： 29 - 37 2005年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Clinical Biochemistry and Nutrition

The aim of the present study was to determine whether imidapril, an angiotensin-converting enzyme inhibitor, prevents diabetic nephropathy and to determine the effect of imidapril on oxidative damage in the diabetic glomeruli in mice. We used female BKS.cg-m+Leprdb/+Leprdb (db/db) mice, a rodent model of type 2 diabetes, and their non-diabetic db/m littermates. The mice were divided into the following four groups: non-diabetic db/m, diabetic db/db, and diabetic db/db treated with imidapril at doses of 1 mg/kg and 5 mg/kg. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were performed for 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the imidapril-treated group and the non-treated db/db group. The systolic blood pressure was significantly increased in db/db mice compared with db/m mice. The increased blood pressure was significantly reduced by the treatment with imidapril at a dose of 5 mg/kg. The relative mesangial area calculated by the mesangial area/total glomerular area ratio was significantly ameliorated in the imidapril-treated group compared with the non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with imidapril in a dose-dependent manner. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than in the imidapril-treated db/db mice. In conclusion, imidapril prevented the progression of diabetic nephropathy in mice, not only by decreasing the glomerular pressure but also by decreasing the oxidative stress in glomerular cells.

DOI： 10.3164/jcbn.37.29

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Susceptibility of actin to modification by 4-hydroxy-2-nonenal. 査読有り国際誌

Ozeki M, Miyagawa-Hayashino A, Akatsuka S, Shirase T, Lee WH, Uchida K, Toyokuni S

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 827 巻 ( 1 ) 頁： 119 - 26 2005年11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：Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

4-Hydroxy-2-nonenal (HNE), a major lipid peroxidation product, reacts with histidine, lysine or cysteine residues of proteins to form hemiacetal Michael adducts and thus interferes with the functions of the proteins. Here we undertook to identify HNE-modified proteins in the target organ of a ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis model with histidine-specific HNEJ-2 antibody. Immunoaffinity column separation and sequencing identified one of the major modified proteins as actin. To further explore the characteristics of actin as an HNE acceptor, we produced four novel monoclonal antibodies against HNE-modified keyhole limpet hemocyanin. All these antibodies (HNEJ-1, 3-5) recognized histidine adducts, but were different from HNEJ-2 in recognizing lysine and cysteine adducts to some extent. Actin, albumin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), metallothionein and superoxide dismutase were treated in vitro with HNE and evaluated with these antibodies. The results revealed that actin was most sensitive to HNE modification and metallothionein most resistant. Furthermore, the residue-specificity of GAPDH was in accord with that shown by our recent mass spectrometry data. Immunohistochemistry with the antibodies revealed cytoplasmic staining with or without nuclear staining in the renal proximal tubules after Fe-NTA administration. The results suggest that actin is a major target protein for HNE modification in vivo, and that our monoclonal antibodies are useful for evaluating the HNE adducts produced. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jchromb.2005.02.025

Susceptibility of actin to modification by 4-hydroxy-2-nonenal

OZEKI Munetaka, MIYAGAWA HAYASHINO Aya, AKATSUKA Shinya, SHIRASE Tomoyuki, LEE Wen-hua, UCHIDA Koji, TOYOKUNI Shinya

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 827 巻 ( 1 ) 頁： 119 - 126 2005年11月

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p35

Yajima N, Yamada S, Morisaki T, Toyokuni S, Yonehara S, Sakamaki K

TRANSGENIC RESEARCH 14 巻 ( 5 ) 頁： 593 - 604 2005年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Transgenic Research

Baculovirus p35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficent animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development. © Springer 2005.

DOI： 10.1007/s11248-005-4350-5

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PubMed

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p 35. 国際誌

Nobuyuki Yajima, Shu-Ichi Yamada, Takayuki Morisaki, Shinya Toyokuni, Shin Yonehara, Kazuhiro Sakamaki

Transgenic research 14 巻 ( 5 ) 頁： 593 - 604 2005年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Baculovirus p 35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p 35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficient animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p 35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p 35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development.

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Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1. 国際誌 Open Access

Kawasaki K, Nishio A, Nakamura H, Uchida K, Fukui T, Ohana M, Yoshizawa H, Ohashi S, Tamaki H, Matsuura M, Asada M, Nishi T, Nakase H, Toyokuni S, Liu W, Yodoi J, Okazaki K, Chiba T

Laboratory investigation; a journal of technical methods and pathology 85 巻 ( 9 ) 頁： 1104 - 17 2005年9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：Laboratory Investigation

Thioredoxin-1 (TRX-1) is a redox-active protein involved in scavenging reactive oxygen species and regulating redox-sensitive transcription factors. TRX-1 is induced in various inflammatory conditions and shows cytoprotective action. We investigated the roles of TRX-1 in the host defense mechanism against Helicobacter felis (H. felis) infection. Transgenic (TG) mice overexpressing human TRX-1 and wild-type (WT) mice were orally inoculated with H. felis. After 2 months, histology, oxidative damage, and gene expression of several cytokines, including macrophage inflammatory protein-2 (MIP-2), a murine equivalent to interleukin (IL)-8, in the gastric mucosa were investigated. Furthermore, the effects of TRX-1 on oxidative stress and neutrophil migration were studied both in vivo and in vitro. The gastric mucosa was thickened in H. felis-infected WT mice, but not in infected TRX-1-TG mice. Histologically, all H. felis-infected WT mice developed moderate-to-severe gastritis, whereas the development of gastritis was significantly suppressed in infected TRX-1-TG mice. Oxidative damage markers, 8-hydroxy-2′-deoxyguanosine and malondialdehyde, increased in the stomach of infected WT mice, but not TRX-1-TG mice. Upregulation of IL-1β and tumor necrosis factor-α gene expression in H. felis-infected TRX-1-TG mice was significantly lower than in WT mice. However, upregulation of MIP-2 and IL-7 was not different between the two groups. TRX-1 suppressed oxidative cytotoxicity and DNA damage, and inhibited neutrophil migration both in vivo and in vitro. The present study suggests that overexpression of TRX-1 suppresses H. felis-induced gastritis by inhibiting chemotaxis of neutrophils and reducing oxidative stress. © 2005 USCAP, Inc All Rights Reserved.

DOI： 10.1038/labinvest.3700305

Genetic and epigenetic properties of mouse male germline stem cells during long-term culture. 査読有り国際誌

Kanatsu-Shinohara M, Ogonuki N, Iwano T, Lee J, Kazuki Y, Inoue K, Miki H, Takehashi M, Toyokuni S, Shinkai Y, Oshimura M, Ishino F, Ogura A, Shinohara T

Development (Cambridge, England) 132 巻 ( 18 ) 頁： 4155 - 63 2005年9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

Although stem cells are believed to divide infinitely by self-renewal division, there is little evidence that demonstrates their infinite replicative potential. Spermatogonial stem cells are the founder cell population for spermatogenesis. Recently, in vitro culture of spermatogonial stem cells was described. Spermatogonial stem cells can be expanded in vitro in the presence of glial cell line-derived neurotrophic factor (GDNF), maintaining the capacity to produce spermatogenesis after transplantation into testis. Here, we examined the stability and proliferative capacity of spermatogonial stem cells using cultured cells. Spermatogonial stem cells were cultured over 2 years and achieved ∼1085-fold expansion. Unlike other germline cells that often acquire genetic and epigenetic changes in vitro, spermatogonial stem cells retained the euploid karyotype and androgenetic imprint during the 2-year experimental period, and produced normal spermatogenesis and fertile offspring. However, the telomeres in spermatogonial stem cells gradually shortened during culture, suggesting that they are not immortal. Nevertheless, the remarkable stability and proliferative potential of spermatogonial stem cells suggest that they have a unique machinery to prevent transmission of genetic and epigenetic damages to the offspring, and these characteristics make them an attractive target for germline modification.

DOI： 10.1242/dev.02004

Germline niche transplantation restores fertility in infertile mice. 査読有り国際誌 Open Access

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

Human reproduction (Oxford, England) 20 巻 ( 9 ) 頁： 2376 - 82 2005年9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：Human Reproduction

Background: Stem cells interact closely with their microenvironment or niche, and abnormalities in niche compromise the self-renewing tissue. In testis, for example, Sertoli cells interact with germ cells, and defects in Sertoli cells compromises spermatogenesis, leading to male infertility. However, it has not been possible to restore spermatogenesis from endogenous stem cells in infertile testis with environmental defects. Methods and results: When healthy Sertoli cells from infertile white spotting (W) mouse were transplanted into the seminiferous tubules of infertile Steel (Sl) mouse testis that had defective Sertoli cells, spermatogenesis occurred from Sl stem cells in the recipient testis. On average, 1.1% of the recipient tubules showed spermatogenesis. Furthermore, in a microinsemination experiment with germ cells that developed in the testis, we obtained four normal offspring from 114 successfully injected oocytes. Conclusions: This study demonstrates that defects in male germline microenvironment can be corrected by Sertoli cell transplantation. Although further improvements are required to enhance the low efficiency of spermatogenesis, the ability to correct environmental defect by niche transplantation has important implications in developing new strategies for treating incurable disorders in self-renewing tissues. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

DOI： 10.1093/humrep/dei096

Nestin-positive cells in adult pancreas express amylase and endocrine precursor cells

Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

PANCREAS 31 巻 ( 2 ) 頁： 126 - 131 2005年8月

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells.

Ueno H, Yamada Y, Watanabe R, Mukai E, Hosokawa M, Takahashi A, Hamasaki A, Fujiwara H, Toyokuni S, Yamaguchi M, Takeda J, Seino Y

Pancreas 31 巻 ( 2 ) 頁： 126 - 31 2005年8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：Pancreas

The neural precursor cell-specific marker nestin is expressed in fetal and adult pancreas, but its role is not fully understood. Using nestin-enhanced green fluorescent protein (EGFP) transgenic mice and fluorescence activated cell sorter, we characterized nestin-positive cells in adult mice pancreas. EGFP mRNA- and protein-positive cells expressed amylase, a pancreatic exocrine marker. Interestingly, EGFP mRNA-negative and protein-positive cells expressed insulin, glucagon, somatostatin and pancreatic polypeptide, pancreatic endocrine markers. These findings demonstrate that nestin-positive cells comprise a portion of pancreatic exocrine cells and suggest that they can be differentiated into pancreatic endocrine cells. Copyright © 2005 by Lippincott Williams & Wilkins.

DOI： 10.1097/01.mpa.0000172564.80921.f7

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PubMed

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells. 国際誌

Hiroyuki Ueno, Yuichiro Yamada, Rie Watanabe, Eri Mukai, Masaya Hosokawa, Akira Takahashi, Akihiro Hamasaki, Hideya Fujiwara, Shinya Toyokuni, Masahiro Yamaguchi, Jun Takeda, Yutaka Seino

Pancreas 31 巻 ( 2 ) 頁： 126 - 31 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

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Establishment of a diabetic mouse model with progressive diabetic nephropathy.

Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y

The American journal of pathology 167 巻 ( 2 ) 頁： 327 - 36 2005年8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 Pathology

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Iγ) in pancreatic β cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Iγ transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Iγ transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors. Copyright © American Society for Investigative Pathology.

DOI： 10.1016/s0002-9440(10)62978-1

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PubMed

Establishment of a diabetic mouse model with progressive diabetic nephropathy

Inada A, Nagai K, Arai H, Miyazaki J, Nomura K, Kanamori H, Toyokuni S, Yamada Y, Bonner-Weir S, Weir GC, Fukatsu A, Seino Y

AMERICAN JOURNAL OF PATHOLOGY 167 巻 ( 2 ) 頁： 327 - 336 2005年8月

Establishment of a diabetic mouse model with progressive diabetic nephropathy 査読有り

A Inada, K Nagai, H Arai, J Miyazaki, K Nomura, H Kanamori, S Toyokuni, Y Yamada, S Bonner-Weir, GC Weir, A Fukatsu, Y Seino

AMERICAN JOURNAL OF PATHOLOGY 167 巻 ( 2 ) 頁： 327 - 336 2005年8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：AMER SOC INVESTIGATIVE PATHOLOGY, INC

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER I gamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER I gamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER I gamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.

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Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells. 査読有り国際誌 Open Access

Hamahata K, Adachi S, Matsubara H, Okada M, Imai T, Watanabe K, Toyokuni SY, Ueno M, Wakabayashi S, Katanosaka Y, Akiba S, Kubota M, Nakahata T

European journal of pharmacology 516 巻 ( 3 ) 頁： 187 - 96 2005年6月

記述言語：英語掲載種別：学位論文（博士）出版者・発行元：European Journal of Pharmacology

We have previously reported that calcium ionophore A23187 differentially induces necrosis in CEM cells, a T-lymphoblastic leukemia cell line, and apoptosis in HL60 cells, a promyelocytic leukemia cell line. Stimulation with VP16, however, induces typical apoptosis in both cell lines. Necrosis in CEM cells, characterized by cell shrinkage and clustering, began within 5 min of treatment. Swelling of the mitochondria, lumpy chromatin condensation and intact plasma membranes were evident by electron microscopy. These A23187-mediated changes in CEM cells were suppressed by clonazepam or CGP37157, inhibitors of the mitochondrial Na+/Ca2+ exchanger. The changes, however, were not affected by cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. In both CEM and HL60 cells, intra-cellular calcium increased with similar amplitude within 1 min of treatment with 2 μM A23187. Intra-mitochondrial calcium increased with clonazepam pre-treatment alone in both CEM and HL60 cells. However, intra-mitochondrial calcium did not change drastically in response to A23187 in CEM or HL60 cells, either untreated or pre-treated with clonazepam. A23187 induces necrosis in CEM cells concurrent with mitochondrial dysfunction, which is independent of the mitochondrial permeability transition, but affected by intra-mitochondrial calcium, while HL60 cells lack these early changes. Differences in the responses to A23187 between these two cell lines might derive from differences in the susceptibility of the mitochondrial membrane to rapid increases in intra-cellular calcium. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2005.04.018

Annexin II overexpression correlates with a poor prognosis in surgically resected non-small-cell lung cancer.

Ichikawa, M; Mio, T; Toyokuni, S; Tanaka, F; Wada, H; Mishima, M; Yanagihara, K

JOURNAL OF CLINICAL ONCOLOGY 23 巻 ( 16 ) 頁： 682S - 682S 2005年6月

Annexin II overexpression correlates with a poor prognosis in surgically resected non-small-cell lung cancer. 査読有り国際誌

Ichikawa, M, Mio, T, Toyokuni, S, Tanaka, F, Wada, H, Mishima, M, Yanagihara, K

JOURNAL OF CLINICAL ONCOLOGY 23 巻 ( 16 ) 頁： 682S - 682S 2005年6月

Two distinct mechanisms for loss of thioredoxin-binding protein-2 in oxidative stress-induced renal carcinogenesis. 査読有り国際誌 Open Access

Dutta KK, Nishinaka Y, Masutani H, Akatsuka S, Aung TT, Shirase T, Lee WH, Yamada Y, Hiai H, Yodoi J, Toyokuni S

Laboratory investigation; a journal of technical methods and pathology 85 巻 ( 6 ) 頁： 798 - 807 2005年6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：Laboratory Investigation

Thioredoxin is a major component of thiol-reducing system. Recently, we identified thioredoxin-binding protein-2 (TBP-2) as a negative regulator of thioredoxin. Here, we report the role of TBP-2 in oxidative renal tubular injury and the subsequent carcinogenesis by ferric nitrilotriacetate. TBP-2 was abundantly expressed in the rat kidney. Immunohistochemical analysis revealed that TBP-2 was present in association with nuclei and mitochondrial intermembrane space in the proximal tubular cells and coimmunoprecipitated with cytochrome c. After acute oxidative tubular damage, TBP-2 protein, but not messenger RNA, markedly decreased, demonstrating shortened half-life of this protein. Most cases of the induced renal cell carcinoma showed undetectable levels of TBP-2 protein, which was associated with the methylation of CpG island in the promoter region. Genome sequence analyses identified the poly-A tract in the 3′ untranslated region as a mutation hot spot in this rather nonselective environment. Collectively, the amounts of TBP-2 protein were inversely associated with proliferation of tubular cells, as evaluated by proliferating cell nuclear antigen. These results suggest that loss of TBP-2 is essential for proliferation of not only neoplastic but also non-neoplastic renal tubular cells, and that TBP-2 is a target gene in oxidative stress-induced renal carcinogenesis by ferric nitrilotriacetate. © 2005 USCAP, Inc All rights reserved.

DOI： 10.1038/labinvest.3700280

Transcriptional control of fetal liver hematopoiesis: dominant negative effect of the overexpression of the LIM domain mutants of LMO2. 査読有り国際誌 Open Access

Terano T, Zhong Y, Toyokuni S, Hiai H, Yamada Y

Experimental hematology 33 巻 ( 6 ) 頁： 641 - 51 2005年6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：Experimental Hematology

Objective. The LIM-finger protein LMO2 forms a transcription factor complex with other hematopoietic regulator proteins, such as TAL1 (SCL), LDB1, GATA1, 2, and 3, in the promoters of several erythroid genes. To elucidate the functional role of two LIM domains in LMO2, we introduced deletion or mutation in each of the LIM domains and analyzed their phenotypic effects on the hematopoietic system when overexpressed in vivo or in vitro. Materials and Methods. Protein interactions of LIM-modified LMO2 constructs with TAL1, LDB1, and GATAs were examined in an immunoprecipitation assay. In vivo hematopoiesis in transgenic mice with wild-type and LIM-modified Lmo2 was studied morphologically and by measuring the progenitor cells in fetal liver. Their effects on the erythroid differentiation of the dimethylsulfoxide (DMSO)-induced murine erythroleukemia (MEL) cells were evaluated. Results. Deletion of the LIM2 domain, but not of the LIM1 domain, abolished its binding of GATA proteins. Overexpression of wild-type LMO2 is known to have dominant negative inhibitory effects on erythropoietic development. Enforced expression of LMO2 constructs with mutant or absent LIM2 but with an intact LIM1 domain resulted in fetal death, small livers and hearts, and decreased hematopoiesis, as well as a hypoplastic thymus. DMSO-induced erythroid differentiation of the MEL cells was inhibited by the overexpressed LMO2 with mutant LIM2 but not by the LMO2 with modified LIM1. Conclusion. Overexpression of the LMO2 with modified LIM2 inhibited hematopoiesis probably by interfering with the formation of the physiological complex or by replacing the functional LMO2 with mutants with reduced affinity to GATA proteins. In this experiment, no evident effect of the LMO2 with modified LIM1 could be observed. © 2005 International. Society for Experimental Hematology. Published by Elsevier Inc.

DOI： 10.1016/j.exphem.2005.01.018

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論文 - 豊國 伸哉

<豊國　伸哉>

論文 - 豊國　伸哉