九州大学 研究者情報
論文一覧
中別府 雄作(なかべっぷ ゆうさく) データ更新日:2018.01.15

教授 /  生体防御医学研究所 個体機能制御学部門 脳機能制御学分野


原著論文
1. Masahiro Shijo, Hiroyuki Honda, Satoshi O Suzuki, Hideomi Hamasaki, Masaaki Hokama, ABOLHASSANI NONA, Yusaku Nakabeppu, Toshiharu Ninomiya, Toru Iwaki, Association of Adipocyte Enhancer-Binding Protein 1 with Alzheimer's Disease Pathology in Human Hippocampi, Brain Pathol, 10.1111/bpa.12475, 28, 58-71, 2018.01.
2. Erika Castillo, Julio Leon, Guianfranco Mazzei, Nona Abolhassani, Naoki Haruyama, Takashi Saito, Takaomi Saido, Masaaki Hokama, Toru Iwaki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Kunihiko Sakumi, Frank M LaFerla, Yusaku Nakabeppu, Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation, Scientific Reports, 10.1038/s41598-017-17999-3, 7, 1, 17762, 2017.12, [URL], Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid beta (Abeta) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Abeta pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App (NL-G-F/NL-G-F) and 3xTg-AD-H mouse models. Genes commonly altered in App (NL-G-F/NL-G-F) and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App (NL-G-F/NL-G-F) cortex as Abeta amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App (NL-G-F/NL-G-F) cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Abeta amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD..
3. Guang Hua Li, Shinya Akatsuka, Shan-Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni, Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model, Pathol Int, 10.1111/pin.12598, 67, 11, 564-574, 2017.11, [URL].
4. Koji Chikama, HidetakaYamada, TatsuoTsukamoto, Kosuke Kajitani, Yusaku Nakabeppu, Naohisa Uchimura, Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse, Brain Res, 10.1016/j.brainres.2017.09.006, 1676, 77-82, 2017.09, [URL].
5. Marco Seifermann, Alexander Ulges, Tobias Bopp, Svetlana Melcea, Andrea Schafer, Sugako Oka, Yusaku Nakabeppu, Arne Klungland, Christof Niehrs, Bernd Epe, Role of the DNA repair glycosylase OGG1 in the activation of murine splenocytes.
, DNA repair, 10.1016/j.dnarep.2017.08.005, 58, 13-20, 2017.08, [URL], OGG1 (8-oxoguanine-DNA glycosylase) is the major DNA repair glycosylase removing the premutagenic DNA base modification 8-oxo-7,8-dihydroguanine (8-oxoG) from the genome of mammalian cells. In addition, there is accumulating evidence that OGG1 and its substrate 8-oxoG might function in the regulation of certain genes, which could account for an attenuated immune response observed in Ogg1(-/-) mice in several settings. Indications for at least two different mechanisms have been obtained. Thus, OGG1 could either act as an ancillary transcription factor cooperating with the lysine-specific demethylase LSD1 or as an activator of small GTPases. Here, we analysed the activation by lipopolysaccaride (LPS) of primary splenocytes obtained from two different Ogg1(-/-) mouse strains. We found that the induction of TNF-alpha expression was reduced in splenocytes (in particular macrophages) of both Ogg1(-/-) strains. Notably, an inhibitor of LSD1, OG-L002, reduced the induction of TNF-alpha mRNA in splenocytes from wild-type mice to the level observed in splenocytes from Ogg1(-/-) mice and had no influence in the latter cells. In contrast, inhibitors of the MAP kinases p38 and JNK as well as the antioxidant N-acetylcysteine attenuated the LPS-stimulated TNF-alpha expression both in the absence and presence of OGG1. The free base 8-oxo-7,8-dihydroguanine had no influence on the TNF-alpha expression in the splenocytes. The data demonstrate that OGG1 plays a role in an LSD1-dependent pathway of LPS-induced macrophage activation in mice..
6. Takatoshi Fujishita, Tatsuro Okamoto, Takaki Akamine, Shinkichi Takamori, Kazuki Takada, Masakazu Katsura, Goji Toyokawa, Fumihiro Shoji, Mototsugu Shimokawa, Yoshinao Oda, Yusaku Nakabeppu, Yoshihiko Maehara, Association of MTH1 expression with the tumor malignant potential and poor prognosis in patients with resected lung cancer., Lung Cancer, 10.1016/j.lungcan.2017.04.012, 109, 52-57, 2017.07, [URL], OBJECTIVES: The oxidized purine nucleoside triphosphatase, mutT homolog 1 (MTH1), physiologically sanitizes 8-oxo-dGTP in the nucleotide pool. Previous studies indicated that MTH1 is associated with tumor proliferation and invasion in non-small cell lung cancer (NSCLC) cell lines; however, the role of MTH1 in patients with NSCLC remains unclear. MATERIALS AND METHODS: Two patient cohorts that underwent surgery for NSCLC in our institution were investigated retrospectively. In one cohort consisting of 197 patients, the associations between MTH1 expression and clinicopathological factors or prognosis were analyzed. In another cohort consisting of 41 patients, the relationship between MTH1 expression in the tumors and serum oxidative stress levels (evaluated by the diacron-reactive oxygen metabolites [d-ROMs] test) or antioxidant capacity in the patients (evaluated by the biological antioxidant potential (BAP) test) was analyzed. A total of 238 patients were assessed for MTH1 protein levels using immunohistochemistry. RESULTS: Among the 197 patients in the former cohort, 111 (56.3%) exhibited high MTH1 expression, while 86 (43.7%) exhibited low MTH1 expression. Male sex, smoking habit of >/=20 pack-years, squamous cell carcinoma, pathological stage >/= II, tumor diameter >/=30mm, lymph node metastases, pleural invasion, lymphatic permeation and vascular infiltration were significantly associated with high MTH1 expression (p<0.05). The high MTH1 expression group had a significantly worse prognosis than that of the low MTH1 expression group (5-year overall survival: 81.6% vs. 92.3%, p=0.0011; 5-year disease-free survival: 55.0% vs. 83.7%, p=0.0002). d-ROMs and BAP test values were significantly higher in the high than in the low MTH1 expression group (p<0.05). CONCLUSION: This study showed that MTH1 protein expression was closely related to factors associated with a high malignant potential and poor patient survival. MTH1 may be a novel therapeutic target for NSCLC..
7. Kosuke Kajitani, Kazuyuki Yanagimoto, Yusaku Nakabeppu, Serum galectin-3, but not galectin-1, levels are elevated in schizophrenia: implications for the role of inflammation, Psychopharmacology, 10.1007/s00213-017-4683-9, 2017.07, [URL], BACKGROUND:
Previous studies have reported that galectin-3 is involved in inflammatory processes in the central nervous system and that neuroinflammation may play a role in the pathogenesis of schizophrenia. However, the link between schizophrenia and various galectins is unclear.
OBJECTIVE:
The objective of the present study is to determine whether galectin, a well-known lectin protein that binds to μ-galactoside, is associated with chronic schizophrenia.
METHODS:
Thirty-six patients with schizophrenia and 36 healthy controls participated in this study. Schizophrenia symptoms were assessed using the Brief Psychiatry Rating Scale (BPRS). Serum galectin-1 and galectin-3 levels were evaluated using ELISA and compared between the participant groups. Correlation analyses were also performed to examine the relationship between BPRS scores and each galectin level.
RESULTS:
Serum galectin-3 levels were significantly higher in patients with schizophrenia than they were in controls (p = 0.009, d = 0.640); however, serum galectin-1 levels were not significantly different between the groups (p = 0.513). No significant correlation was identified between serum galectin-3 level and the total BPRS score; however, a significant positive correlation was found between the serum galectin-3 level and the positive symptom score of the BPRS (ρ = 0.355; p = 0.033). Additionally, a significant negative correlation was identified between serum galectin-3 levels and the negative symptom score of the BPRS (ρ = -0.387; p = 0.020).
CONCLUSIONS:
Given the high serum levels of galectin-3 found in patients with schizophrenia compared with that in controls, these findings may support the inflammation hypothesis of schizophrenia..
8. Vladimir Vartanian, Jana Tumova, Pawel Dobrzyn, Yusaku Nakabeppu, R. Stephen Lloyd, Harini Sampath, 8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle, PLos One, 10.1371/journal.pone.0181687, 12, 7, e0181687, 2017.07, [URL], Oxidative stress resulting from endogenous and exogenous sources causes damage to cellular components, including genomic and mitochondrial DNA. Oxidative DNA damage is primarily repaired via the base excision repair pathway that is initiated by DNA glycosylases. 8-oxoguanine DNA glycosylase (OGG1) recognizes and cleaves oxidized and ring-fragmented purines, including 8-oxoguanine, the most commonly formed oxidative DNA lesion. Mice lacking the OGG1 gene product are prone to multiple features of the metabolic syndrome, including high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Here, we report that OGG1-deficient mice also display skeletal muscle pathologies, including increased muscle lipid deposition and alterations in genes regulating lipid uptake and mitochondrial fission in skeletal muscle. In addition, expression of genes in the TCA cycle and carbohydrate and lipid metabolism are also significantly altered in muscle of OGG1-deficient mice. These tissue changes are accompanied by marked reductions in markers of muscle function in OGG1-deficient animals, including decreased grip strength and treadmill endurance. Collectively, these data indicate a role for repair of oxidative DNA damage in skeletal muscle in the maintenance of optimal tissue function..
9. Shinji Asada, Eiko Ohta, Yoriko Akimoto, ABOLHASSANI NONA, Daisuke Tsuchimoto, Yusaku Nakabeppu, 2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway, Scientific Reports, 10.1038/s41598-017-06636-8, 7, 1, 6528, 2017.07, [URL], 2-Oxoadenosine (2-oxo-Ado), an oxidized form of adenosine, is cytotoxic and induces growth arrest and cell death, which has potential as an anti-cancer drug. However, it is not well understood how 2-oxo-Ado exerts its cytotoxicity. We examined the effects of 2-oxo-Ado on non-tumour cells, namely immortalized mouse embryonic fibroblast lines, and investigated mechanisms by which 2-oxo-Ado exerts its cytotoxicity. We found that cell death induced by 2-oxo-Ado is classical caspase-dependent apoptosis, and requires its sequential intracellular phosphorylation catalysed by adenosine kinase (ADK) and adenylate kinase 2, resulting in intracellular accumulation of 2-oxo-ATP accompanied by accumulation of 2-oxo-Ado in RNA and depletion of ATP. Moreover, we showed that overexpression of MTH1, an oxidized purine nucleoside triphosphatase, prevents 2-oxo-Ado-induced cytotoxicity accompanied by suppression of accumulation of both intracellular 2-oxo-ATP and 2-oxo-Ado in RNA and recovery of ATP levels. We also found that 2-oxo-Ado activates the p38 MAPK pathway. However, siRNAs against Mkk3 and Mkk6, or treatment with several p38 MAPK inhibitors, except SB203580, did not prevent the cytotoxicity. SB203580 prevented intracellular phosphorylation of 2-oxo-Ado to 2-oxo-AMP, and an in vitro ADK assay revealed that SB203580 directly inhibits ADK activity, suggesting that some of the effects of SB203580 may depend on ADK inhibition..
10. Nona Abolhassani, Julio Leon, Zijing Sheng, Sugako Oka, Hideomi Hamasaki, Toru Iwaki, Yusaku Nakabeppu, Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain, Mech Ageing Dev, 10.1016/j.mad.2016.05.005, 161, 95-104, 2017.05, [URL], In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8-oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality last long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia..
11. Yusuke Yoshii, Taikai Inoue, Yuya Uemura, Yusaku Iwasaki, Toshihiko Yada, Yusaku Nakabeppu, Mami Noda, Complexity of Stomach-Brain Interaction Induced by Molecular Hydrogen in Parkinson's Disease Model Mice, Neurochem Res, 10.1007/s11064-017-2281-1, 2017.05, [URL].
12. Chihiro Takemori, Makoto Kunisada, Flandiana Yogianti, Sugako Oka, SAKUMI Kunihiko, Ryusuke Ono, Yusaku Nakabeppu, Chikako Nishigori, Co-regulation of Cxcl1 and versican in the inflammatory response to UVB induced reactive oxygen species in skin photo-tumorigenesis, J Dermatol Sci, 10.1016/j.jdermsci.2016.10.011, 85, 2, 140-143, 2017.02, [URL].
13. Shaimaa Waz, Teruya Nakamura, Keisuke Hirata, Yukari Koga Ogawa, Mami Chirifu, Takao Arimori, Taro Tamada, Shinji Ikemizu, Yusaku Nakabeppu, Yuriko Yamagata, Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity, J Biol Chem, 10.1074/jbc.M116.749713, 292, 7, 2785-2794, 2017.02, [URL].
14. Issei Egashira, Fumi Takahashi-Yanaga, Risa Nishida, Masaki Arioka, Kazunobu Igawa, KatsuhikoTomooka, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yusaku Nakabeppu, Takanari Takanari, Toshiyuki Toshiyuki, Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/beta-catenin signaling pathway, Cancer Sci, 10.1111/cas.13106, 108, 1, 108-115, 2017.01, [URL], We previously reported that celecoxib, a selective COX-2 inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/beta-catenin signaling pathway. 2,5-Dimethylcelecoxib (DM-celecoxib), a celecoxib analog that does not inhibit COX-2, has also been reported to have an antitumor effect. In the present study, we elucidated whether DM-celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM-celecoxib with that of celecoxib on the human colon cancer cell lines HCT-116 and DLD-1. 2,5-Dimethylcelecoxib suppressed cell proliferation and inhibited T-cell factor 7-like 2 expression with almost the same strength as celecoxib. 2,5-Dimethylcelecoxib also inhibited the T-cell factor-dependent transcription activity and suppressed the expression of Wnt/beta-catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM-celecoxib using the Mutyh-/- mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM-celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated treatment with celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer effect of celecoxib derivatives is the suppression of the Wnt/beta-catenin signaling pathway but not the inhibition of COX-2, and that DM-celecoxib might be a better lead compound candidate than celecoxib for the development of novel anticancer drugs..
15. Shingo Akiyama, Hiroshi Saeki, Yuichiro Nakashima, Makoto Imori, Hiroyuki Kitao, Eiji Oki, Yoshinao Oda, Yusaku Nakabeppu, Yoshihiro Kakeji, Yoshihiko Maehara, Prognostic impact of MutT homolog-1 expression on esophageal squamous cell carcinoma, Cancer Medicine, 10.1002/cam4.979, 6, 1, 258-266, 2017.01, [URL], MutT homolog-1 (MTH1) is a pyrophosphatase that acts on oxidized nucleotides and hydrolyzes 8-oxo-2'-deoxyguanosine triphosphate in deoxynucleoside triphosphate pool to prevent its incorporation into nuclear and mitochondrial DNA, result in reduce cytotoxicity in tumor cells. MTH1 is overexpressed in various cancers and is considered as a therapeutic target. Environmental factors such as cigarette smoking and alcohol consumption are critical risk factors for the development and progression of esophageal squamous cell carcinoma (ESCC), suggesting that oxidative stress contributes to the pathogenesis of ESCC. We examined the expression of MTH1 and the accumulation of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in 84 patients with ESCC who underwent curative resection without neoadjuvant therapy. MTH1 mRNA level was quantified by performing quantitative reverse transcription-PCR. Immunohistochemical analysis of paraffin-embedded cancer tissues was performed to determine MTH1 protein expression and 8-oxo-dG accumulation. MTH1 mRNA expression was higher in cancerous tissues than in the corresponding normal epithelium (P < 0.0001). Immunohistochemical analysis showed that high MTH1 expression was significantly associated with deeper tumor invasion and venous invasion, advanced cancer stage, and poor overall survival (P = 0.0021) and disease-specific survival (P = 0.0013) compared with low MTH1 expression. Furthermore, high MTH1 expression was an independent predictor of poor disease-specific survival (P = 0.0121). In contrast, 8-oxo-dG accumulation was not associated with any clinicopathological factor and poor prognosis. These results suggest that MTH1 overexpression is a predictor of ESCC progression and poor prognosis and that MTH1 can serve as a therapeutic target for treating patients with ESCC..
16. Michel Massaad, Jia Zhou, Daisuke Tsuchimoto, Janet Chou, Haifa Jabara, Erin Janssen, Salome Glauzy, Brennan G. Olson, Henner Morbach, Toshiro Ohsumi, Klaus SchmitzAbe, Markianos Kyriacos, Jennifer Kane, Kumiko Torisu, Yusaku Nakabeppu, Luigi D. Notarangelo, Eliane Chouery, André Megarbane, Peter B. Kang, Deficiency of the base excision repair enzyme NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies and predisposition to autoimmunity, J Clin Invest, 10.1172/JCI85647., 126, 11, 4219-4236, 2016.11, [URL], Alterations in the apoptosis of immune cells have been associated with autoimmunity. Three siblings in a consanguineous family suffered from fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function. Whole genome sequencing identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIIIlike3 (NEIL3) that abolished enzymatic activity. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who was found to have elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed absence of LPSresponsive
beigelike anchor (LRBA) protein expression, a known cause of immunodeficiency. To determine the contribution of NEIL3 to the maintenance of selftolerance, we examined Neil3-/- mice. Neil3-/- mice had normal B cell function, but exhibited elevated serum levels of autoantibodies, and developed nephritis following treatment with polyI:C to mimic microbial stimulation. Splenic T and B cells, and germinal center B cells from the Peyer’s patches of Neil3-/- mice showed significantly increased apoptosis/death, potentially releasing selfantigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies and predisposition to autoimmunity..
17. Sugako Oka, Julio Leon, Kunihiko Sakumi, Tomomi Ide, Dongchon Kang, Frank M LaFerla, Yusaku Nakabeppu, Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease, Sci Rep, 10.1038/srep37889, 6, 37889, 2016.11, [URL], In the mitochondria-mediated vicious cycle of Alzheimer's disease (AD), intracellular amyloid beta (Abeta) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Abeta accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Abeta in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Abeta aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1(P117L) gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Abeta. These results provide new insights into potential novel therapeutic targets..
18. Kumiko Torisu, Xueli Zhang, Mari Nonak, Takahide Kaji, Daisuke Tsuchimoto, Kosuke Kajitani, SAKUMI Kunihiko, Torisu Takehiro, Kazuhiro Chida, Katsuo Sueishi, Michiaki Kubo, Jun Hata, Kitazono T, Yutaka Kiyohara, Yusaku Nakabeppu, PKCη deficiency improves lipid metabolism and atherosclerosis in apolipoprotein E-deficient mice, Genes to Cells, 10.1111/gtc.12402, 21, 10, 1030-1048, 2016.10, [URL], Genomewide association studies have shown that a nonsynonymous single nucleotide polymorphism in PRKCH is associated with cerebral infarction and atherosclerosis-related complications. We examined the role of PKCeta in lipid metabolism and atherosclerosis using apolipoprotein E-deficient (Apoe-/- ) mice. PKCeta expression was augmented in the aortas of mice with atherosclerosis and exclusively detected in MOMA2-positive macrophages within atherosclerotic lesions. Prkch+/+ Apoe-/- and Prkch-/- Apoe-/- mice were fed a high-fat diet (HFD), and the dyslipidemia observed in Prkch+/+ Apoe-/- mice was improved in Prkch-/- Apoe-/- mice, with a particular reduction in serum LDL cholesterol and phospholipids. Liver steatosis, which developed in Prkch+/+ Apoe-/- mice, was improved in Prkch-/- Apoe-/- mice, but glucose tolerance, adipose tissue and body weight, and blood pressure were unchanged. Consistent with improvements in LDL cholesterol, atherosclerotic lesions were decreased in HFD-fed Prkch-/- Apoe-/- mice. Immunoreactivity against 3-nitrotyrosine in atherosclerotic lesions was dramatically decreased in Prkch-/- Apoe-/- mice, accompanied by decreased necrosis and apoptosis in the lesions. ARG2 mRNA and protein levels were significantly increased in Prkch-/- Apoe-/- macrophages. These data show that PKCeta deficiency improves dyslipidemia and reduces susceptibility to atherosclerosis in Apoe-/- mice, showing that PKCeta plays a role in atherosclerosis development..
19. Yasuto Yoneshima, Nona Abolhassani, Teruaki Iyama, Kunihiko Sakumi, Naoko Shiomi, Masahiko Mori, Tadahiro Shiomi, Tetsuo Noda, Daisuke Tsuchimoto, Yusaku Nakabeppu, Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells, Sci Rep, 10.1038/srep32849, 6, 32849, 2016.09, [URL].
20. Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh-Hei Sonoda, MUTYH promotes oxidative microglial activation and inherited retinal degeneration, JCI Insight, 10.1172/jci.insight.87781, 1, 15, e87781, 2016.09, [URL].
21. Mark D Evans, Vilas Mistry, Rajinder Singh, Daniel Gackowski, Rafal Rozalski, Agnieszka Siomek-Gorecka, David H Phillips, Jie Zuo, Leon Mullenders, Alex Pines, Yusaku Nakabeppu, Kunihiko Sakumi, Mutsuo Sekiguchi, Teruhisa Tsuzuki, Margherita Bignami, Ryszard Olinski, Marcus S Cooke, Nucleotide excision repair of oxidised genomic DNA is not a source of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine, Free Radic Biol Med, 10.1016/j.freeradbiomed.2016.08.018, 99, 385-391, 2016.08, [URL], Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a widely measured biomarker of oxidative stress. It has been commonly assumed to be a product of DNA repair, and therefore reflective of DNA oxidation. However, the source of urinary 8-oxodGuo is not understood, although potential confounding contributions from cell turnover and diet have been ruled out. Clearly it is critical to understand the precise biological origins of this important biomarker, so that the target molecule that is oxidised can be identified, and the significance of its excretion can be interpreted fully. In the present study we aimed to assess the contributions of nucleotide excision repair (NER), by both the global genome NER (GG-NER) and transcription-coupled NER (TC-NER) pathways, and sanitisation of the dGTP pool (e.g. via the activity of the MTH1 protein), on the production of 8-oxodGuo, using selected genetically-modified mice. In xeroderma pigmentosum A (XPA) mice, in which GG-NER and TC-NER are both defective, the urinary 8-oxodGuo data were unequivocal in ruling out a contribution from NER. In line with the XPA data, the production of urinary 8-oxodGuo was not affected in the xeroderma pigmentosum C mice, specifically excluding a role of the GG-NER pathway. The bulk of the literature supports the mechanism that the NER proteins are responsible for removing damage to the transcribed strand of DNA via TC-NER, and on this basis we also examined Cockayne Syndrome mice, which have a functional loss of TC-NER. These mice showed no difference in urinary 8-oxodGuo excretion, compared to wild type, demonstrating that TC-NER does not contribute to urinary 8-oxodGuo levels. These findings call into question whether genomic DNA is the primary source of urinary 8-oxodGuo, which would largely exclude it as a biomarker of DNA oxidation. The urinary 8-oxodGuo levels from the MTH1 mice (both knock-out and hMTH1-Tg) were not significantly different to the wild-type mice. We suggest that these findings are due to redundancy in the process, and that other enzymes substitute for the lack of MTH1, however the present study cannot determine whether or not the 2'-deoxyribonucleotide pool is the source of urinary 8-oxodGuo. On the basis of the above, urinary 8-oxodGuo is most accurately defined as a non-invasive biomarker of oxidative stress, derived from oxidatively generated damage to 2'-deoxyguanosine..
22. Shizuka Takaku, Naoko Niimi, Toshihiko Kadoya, Hideji Yako, Masami Tsukamoto, Kunihiko Sakumi, Yusaku Nakabeppu, Hidenori Horie, Kazunori Sango, Galectin-1 and galectin-3 as key molecules for peripheral nerve degeneration and regeneration, AIMS Mol Sci, 10.3934/molsci.2016.3.325, 3, 3, 325-337, 2016.07, [URL].
23. Yuki Matsushita, Yasunari Sakai, Mitsunori Shimmura, Hiroshi Shigeto, Miki Nishio, Satoshi Akamine, Masafumi Sanefuji, Yoshito Ishizaki, Hiroyuki Torisu, Yusaku Nakabeppu, Akira Suzuki, Hidetoshi Takada, Toshiro Hara, Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice, Sci Rep, 10.1038/srep22991, 6, 22991, 2016.03, [URL].
24. Julio Leon, Kunihiko Sakumi, Erika Castillo, Zijing Sheng, Sugako Oka, Yusaku Nakabeppu, 8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions., Sci Rep, 10.1038/srep22086, 6, 22086, 2016.02, [URL], Oxidative stress and mitochondrial dysfunction are implicated in aging-related neurodegenerative disorders. 8-Oxoguanine (8-oxoG), a common oxidised base lesion, is often highly accumulated in brains from patients with neurodegenerative disorders. MTH1 hydrolyses 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP) to 8-oxo-dGMP and pyrophosphate in nucleotide pools, while OGG1 excises 8-oxoG paired with cytosine in DNA, thereby minimising the accumulation of 8-oxoG in DNA. Mth1/Ogg1-double knockout (TO-DKO) mice are highly susceptible to neurodegeneration under oxidative conditions and show increased accumulation of 8-oxoG in mitochondrial DNA (mtDNA) in neurons, suggesting that 8-oxoG accumulation in mtDNA causes mitochondrial dysfunction. Here, we evaluated the contribution of MTH1 and OGG1 to the prevention of mitochondrial dysfunction during neuritogenesis in vitro. We isolated cortical neurons from adult wild-type and TO-DKO mice and maintained them with or without antioxidants for 2 to 5 days and then examined neuritogenesis. In the presence of antioxidants, both TO-DKO and wild-type neurons exhibited efficient neurite extension and arborisation. However, in the absence of antioxidants, the accumulation of 8-oxoG in mtDNA of TO-DKO neurons was increased resulting in mitochondrial dysfunction. Cells also exhibited poor neurite outgrowth with decreased complexity of neuritic arborisation, indicating that MTH1 and OGG1 are essential for neuritogenesis under oxidative conditions. .
25. Bjorge, Monica D, Hildrestrand, Gunn A, Scheffler, Katja, Suganthan, Rajikala, Rolseth, Veslemoy, Kusnierczyk, Anna, Rowe, Alexander D, Vagbo, Cathrine B, Vetlesen, Susanne, Eide, Lars, Slupphaug, Geir, Nakabeppu, Yusaku, Bredy, Timothy W, Klungland, Arne, Bjoras, Magnar, Synergistic Actions of Ogg1 and Mutyh DNA Glycosylases Modulate Anxiety-like Behavior in Mice, Cell Reports, 10.1016/j.celrep.2015.12.001, 13, 12, 2671-2678, 2015.12, Ogg1 and Mutyh DNA glycosylases cooperate to prevent mutations caused by 8-oxoG, a major premutagenic DNA lesion associated with cognitive decline. We have examined behavior and cognitive function in mice deficient of these glycosylases. Ogg1(-/-)Mutyh(-/-) mice were more active and less anxious, with impaired learning ability. In contrast, Mutyh(-/-) mice showed moderately improved memory. We observed no apparent change in genomic 8-oxoG levels, suggesting that Ogg1 and Mutyh play minor roles in global repair in adult brain. Notably, transcriptome analysis of hippocampus revealed that differentially expressed genes in the mutants belong to pathways known to be involved in anxiety and cognition. Esr1 targets were upregulated, suggesting a role of Ogg1 and Mutyh in repression of Esr1 signaling. Thus, beyond their involvement in DNA repair, Ogg1 and Mutyh regulate hippocampal gene expression related to cognition and behavior, suggesting a role for the glycosylases in regulating adaptive behavior..
26. Naoya Kubokura, Fumi Takahashi-Yanaga, Masaki Arioka, Tatsuya Yoshihara, Kazunobu Igawa, Katsuhiko Tomooka, Sachio Morimoto, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yusaku Nakabeppu, Takayuki Matsumoto, Takanari Kitazono, Toshiyuki Sasaguri, Differentiation-inducing factor-3 inhibits intestinal tumor growth in vitro and in vivo, J Pharmacol Sci, 10.1016/j.jphs.2015.03.005, 127, 4, 446-455, 2015.04.
27. Yuko Kobayakawa, Kunihiko Sakumi, Kosuke Kajitani, Toshihiko Kadoya, Hidenori Horie, Jun-ichi Kira, Yusaku Nakabeppu, Galectin-1 deficiency improves axonal swelling of motor neurons in SOD1G93A transgenic mice, Neuropathol Appl Neurobiol, 10.1111/nan.12123, 41, 2, 227-244, 2015.02, [URL], Aims: Galectin-1, a member of the β-galactoside-binding lectin family, accumulates in neurofilamentous lesions in the spinal cords of both sporadic and familial amyotrophic lateral sclerosis (ALS) patients with a superoxide dismutase 1 gene (SOD1) mutation (A4V). The aim of this study was to evaluate the roles of endogenous galectin-1 in the pathogenesis of ALS. Methods: Expression of galectin-1 in the spinal cord of mutant SOD1 transgenic (SOD1G93A) mice was examined by pathological analysis, real-time RT-PCR, and western blotting. The effects of galectin-1 deficiency were evaluated by cross-breeding SOD1G93A mice with galectin-1 null (Lgals1-/-) mice. Results: Before ALS-like symptoms developed in SOD1G93A/Lgals1+/+ mice, strong galectin-1 immunoreactivity was observed in swollen motor axons and colocalized with aggregated neurofilaments. Electron microscopic observations revealed that the diameters of swollen motor axons in the spinal cord were significantly smaller in SOD1G93A/Lgals1-/- mice, and there was less accumulation of vacuoles compared with SOD1G93A/Lgals1+/+ mice. In symptomatic SOD1G93A/Lgals1+/+ mice, astrocytes surrounding motor axons expressed a high level of galectin-1. Conclusions: Galectin-1 accumulates in neurofilamentous lesions in SOD1G93A mice, as previously reported in humans with ALS. Galectin-1 accumulation in motor axons occurs before the development of ALS-like symptoms and is associated with early processes of axonal degeneration in SOD1G93A mice. In contrast, galectin-1 expressed in astrocytes may be involved in axonal degeneration during symptom presentation..
28. Sugako Oka, Julio Leon, Daisuke Tsuchimoto, Kunihiko Sakumi, Yusaku Nakabeppu, MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP-dependent cell death, Oncogenesis, 10.1038/oncsis.2014.35, 3, e121, 2014.10, [URL], p53-regulated caspase-independent cell death has been implicated in inhibiting tumorigenesis, however, the regulating mechanisms are poorly understood. We previously reported that 8-oxoguanine (8-oxoG) accumulation in nuclear DNA (nDNA) and mitochondrial DNA (MtDNA) triggers two distinct caspase-independent cell death through buildup of single-strand DNA breaks by MUTYH, an adenine DNA glycosylase. One pathway depends on poly-ADP-ribose polymerase (PARP) and the other depends on calpains. Deficiency of MUTYH causes MUTYH-associated familial adenomatous polyposis. MUTYH thereby suppresses tumorigenesis not only by inhibiting mutagenesis, but also by inducing cell death. Here, we identified the functional p53-binding site in the human MUTYH gene and that demonstrated that MUTYH is transcriptionally regulated by p53, especially in the p53/DNA mismatch repair enzyme, MLH1-proficient colorectal cancer HCT116+Chr3 cells. MUTYH siRNA, an inhibitor for p53 or PARP suppressed cell death without an additive effect, thus revealing that MUTYH is a potential mediator of p53 tumor suppression, which is known to be up-regulated by MLH1. Moreover, we found that p53-proficient, mismatch repair protein, MLH1-proficient colorectal cancer cell lines express substantial levels of MUTYH in nuclei but not in mitochondria, suggesting that 8-oxoG accumulation in nDNA triggers MLH1/PARP-dependent cell death. These results provide new insights on the molecular mechanism of tumorigenesis and potential new strategies for cancer therapies..
29. Flandiana Yogianti, Makoto Kunisada, Eiji Nakano, Ryusuke Ono, Kunihiko Sakumi, Sugako Oka, Yusaku Nakabeppu, Chikako Nishigori, Inhibitory effects of dietary Spirulina platensis on UVB induced skin inflammatory responses and carcinogenesis, J Invest Dermatol, doi: 10.1038/jid.2014.188., 134, 10, 2610-2619, 2014.10.
30. Masaaki Hokama, Sugako Oka, Julio Leon, Toshiharu Ninomiya, HIROYUKI HONDA, Kensuke Sasaki, Toru Iwaki, Tomoyuki Ohara, Tomio Sasaki, Frank M. LaFerla, Yutaka Kiyohara, Yusaku Nakabeppu, Altered expression of diabetes-related genes in Alzheimer’s disease brains: The Hisayama study, Cereb Cortex , 10.1093/cercor/bht101, 24, 9, 2476-2488, 2014.09, [URL], Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM..
31. Hiroko Nomaru, Kunihiko Sakumi, Atsuhisa Katogi, Yoshinori N Ohnishi, Kosuke Kajitani, Daisuke Tsuchimoto, Eric J. Nestler, Yusaku Nakabeppu, Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia, Glia, 10.1002/glia.22680., 62, 8, 1284-1298, 2014.08, [URL], The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no increase in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression..
32. Takuro Isoda, Yoshimichi Nakatsu, Jingshu Piao, Takashi Yao, Hiroshi Honda, Yusaku Nakabeppu, Teruhisa Tsuzuki, Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice, Int. J. Biol. Sci., 10.7150/ijbs.9241, 10, 8, 940-947, 2014.08, MUTYH is a DNA glycosylase that excises adenine paired with 8-oxoguanine to prevent mutagenesis in mammals. Biallelic germline mutations of MUTYH have been found in patients predisposed to a recessive form of familial adenomatous polyposis (MAP: MUTYH-associated polyposis). We previously reported that Mutyh-deficient mice showed a high susceptibility to spontaneous and oxidative stress-induced intestinal adenoma/carcinoma. Here, we performed mutation analysis of the tumor-associated genes including Apc, Ctnnb1, Kras and Trp53 in the intestinal tumors of Mutyh-deficient mice. In the 62 tumors, we identified 25 mutations in Apc of 18 tumors and 36 mutations in Ctnnb1 of 36 tumors. Altogether, 54 out of the 62 tumors (87.1%) had a mutation in either Apc or Ctnnb1; no tumor displayed mutations simultaneously in the both genes. Similar to MAP, 60 out of 61 mutations (98.3%) were identified as G:C to T:A transversions of which 85% occurred at either AGAA or TGAA sequences. Immunohistochemical analyses revealed the accumulation of β-catenin in the nuclei of tumors. No mutation was found in either Kras or Trp53 in the tumors. These results indicate that the uncontrolled activation of Wnt signaling pathway is causatively associated with oxidative stress-induced intestinal tumorigenesis in the Mutyh-deficient mice..
33. Jeroen E J Guikema, Erin K Linehan, Nada Esa, Daisuke Tsuchimoto, Yusaku Nakabeppu, Robert T. Woodland, Carol E. Schrader, Apurinic/Apyrimidinic Endonuclease 2 Regulates the Expansion of Germinal Centers by Protecting against Activation-Induced Cytidine Deaminase-Independent DNA Damage in B Cells, J Immunol, 10.4049/jimmunol.1400002, 193, 2, 931-939, 2014.07, Activation-induced cytidine deaminase (AID) initiates a process generating DNA mutations and breaks in germinal center (GC) B cells that are necessary for somatic hypermutation and class-switch recombination. GC B cells can "tolerate" DNA damage while rapidly proliferating because of partial suppression of the DNA damage response by BCL6. In this study, we develop a model to study the response of mouse GC B cells to endogenous DNA damage. We show that the base excision repair protein apurinic/apyrimidinic endonuclease (APE) 2 protects activated B cells from oxidative damage in vitro. APE2-deficient mice have smaller GCs and reduced Ab responses compared with wild-type mice. DNA double-strand breaks are increased in the rapidly dividing GC centroblasts of APE2-deficient mice, which activate a p53-independent cell cycle checkpoint and a p53-dependent apoptotic response. Proliferative and/or oxidative damage and AID-dependent damage are additive stresses that correlate inversely with GC size in wild-type, AID-, and APE2-deficient mice. Excessive double-strand breaks lead to decreased expression of BCL6, which would enable DNA repair pathways but limit GC cell numbers. These results describe a nonredundant role for APE2 in the protection of GC cells from AID-independent damage, and although GC cells uniquely tolerate DNA damage, we find that the DNA damage response can still regulate GC size through pathways that involve p53 and BCL6..
34. Fumi Takahashi, Tatsuya Yoshihara, Kentaro Jingushi, Kazuhiro Igawa, Katsuhiko Tomooka, Yutaka Watanabe, Sachio Morimoto, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yusaku Nakabeppu, Toshiyuki Sasaguri, DIF-1 inhibits tumor growth in vivo reducing phosphorylation of GSK-3beta and expressions of cyclin D1 and TCF7L2 in cancer model mice, Biochem Pharmacol, 10.1016/j.bcp.2014.03.006., 89, 3, 340-348, 2014.06.
35. Janet Stavnezera, Erin K Linehan, Mikayla R. Thompsona, Robert T. Woodland, Ghaith Habboub, Anna J. Ucher, Tatenda Kadungure, Daisuke Tsuchimoto, Yusaku Nakabeppu, Carol E. Schrader, Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation, Proc Natl Acad Sci U S A, 10.1073/pnas.1405590111, 111, 25, 9217-9222, 2014.06, Somatic hypermutation (SHM) of antibody variable region genes is initiated in germinal center B cells during an immune response by activation-induced cytidine deaminase (AID), which converts cytosines to uracils. During accurate repair in nonmutating cells, uracil is excised by uracil DNA glycosylase (UNG), leaving abasic sites that are incised by AP endonuclease (APE) to create single-strand breaks, and the correct nucleotide is reinserted by DNA polymerase beta. During SHM, for unknown reasons, repair is error prone. There are two APE homologs in mammals and, surprisingly, APE1, in contrast to its high expression in both resting and in vitro-activated splenic B cells, is expressed at very low levels in mouse germinal center B cells where SHM occurs, and APE1 haploinsufficiency has very little effect on SHM. In contrast, the less efficient homolog, APE2, is highly expressed and contributes not only to the frequency of mutations, but also to the generation of mutations at A:T base pair (bp), insertions, and deletions. In the absence of both UNG and APE2, mutations at A:T bp are dramatically reduced. Single-strand breaks generated by APE2 could provide entry points for exonuclease recruited by the mismatch repair proteins Msh2-Msh6, and the known association of APE2 with proliferating cell nuclear antigen could recruit translesion polymerases to create mutations at AID-induced lesions and also at A:T bp. Our data provide new insight into error-prone repair of AID-induced lesions, which we propose is facilitated by down-regulation of APE1 and up-regulation of APE2 expression in germinal center B cells..
36. Hideomi Hamasaki, Hiroyuki Honda, Satoshi O Suzuki, Masaaki Hokama, Yutaka Kiyohara, Yusaku Nakabeppu, Toru Iwaki, Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains, Neuropathology, 10.1111/neup.12095, 34, 3, 284-290, 2014.06, [URL], We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer's disease (AD) patients. Therefore, we tried to determine the cellular component-dependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found marked decline of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up-regulated around senile plaques, beta-amyloid deposition might be associated with astrocytosis through the HGF signaling pathway..
37. Mizuki Ohno, Kunihiko Sakumi, Ryutaro Fukumura, Masato Furuichi, Yuki Iwasaki, Masaaki Hokama, Toshimichi Ikemura, Teruhisa Tsuzuki, Yoichi Gondo, Yusaku Nakabeppu, 8-oxoguanine causes spontaneous de novo germline mutations in mice, Sci Rep, 10.1038/srep04689, 4, 4689, 2014.04, [URL], Spontaneous germline mutations generate genetic diversity in populations of sexually reproductive organisms, and are thus regarded as a driving force of evolution. However, the cause and mechanism remain unclear. 8-oxoguanine (8-oxoG) is a candidate molecule that causes germline mutations, because it makes DNA more prone to mutation and is constantly generated by reactive oxygen species in vivo. We show here that endogenous 8-oxoG caused de novo spontaneous and heritable G to T mutations in mice, which occurred at different stages in the germ cell lineage and were distributed throughout the chromosomes. Using exome analyses covering 40.9 Mb of mouse transcribed regions, we found increased frequencies of G to T mutations at a rate of 2 x 10(-7) mutations/base/generation in offspring of Mth1/Ogg1/Mutyh triple knockout (TOY-KO) mice, which accumulate 8-oxoG in the nuclear DNA of gonadal cells. The roles of MTH1, OGG1, and MUTYH are specific for the prevention of 8-oxoG-induced mutation, and 99% of the mutations observed in TOY-KO mice were G to T transversions caused by 8-oxoG; therefore, we concluded that 8-oxoG is a causative molecule for spontaneous and inheritable mutations of the germ lineage cells..
38. Jalland, C. M., Benestad, S. L., Ersdal, C., Scheffler, K., Suganthan, R., Nakabeppu, Y., Eide, L., Bjoras, M., Tranulis, M. A., Accelerated clinical course of prion disease in mice compromised in repair of oxidative DNA damage, Free Radic Biol Med, 10.1016/j.freeradbiomed.2013.11.013., 68, 1-7, 2014.03, [URL], The detailed mechanisms of prion-induced neurotoxicity are largely unknown. Here, we have studied the role of DNA damage caused by reactive oxygen species in a mouse scrapie model by characterizing prion disease in the ogg1-/-mutyh-/- double knockout, which is compromised in oxidative DNA base excision repair. Ogg1 initiates removal of the major oxidation product 8-oxoguanine (8-oxoG) in DNA, and Mutyh initiates removal of adenine that has been misincorporated opposite 8-oxoG. Our data show that the onset of clinical signs appeared unaffected by Mutyh and Ogg1 expression. However, the ogg1-/-mutyh-/- mice displayed a significantly shorter clinical phase of the disease. Thus, accumulation of oxidative DNA damage might be of particular importance in the terminal clinical phase of prion disease. The prion-induced pathology and lesion profile were similar between knockout mice and controls. The fragmentation pattern of protease-resistant PrP as revealed in Western blots was also identical between the groups. Our data show that the fundamentals of prion propagation and pathological manifestation are not influenced by the oxidative DNA damage repair mechanisms studied here, but that progressive accumulation of oxidative lesions may accelerate the final toxic phase of prion disease..
39. Kajitani, K., Kobayakawa Y., Nomaru, H., Kadoya, T., Horie, H., Nakabeppu, Y., Characterization of galectin-1-positive cells in the mouse hippocampus, NeuroReport, 10.1097/WNR.0000000000000068, 25, 3, 171-176, 2014.02, [URL].
40. Murakami, N., Ohtsubo, T., Kansui, Y., Goto, K., Noguchi, H., Haga, Y., Nakabeppu, Y., Matsumura, K., Kitazono, T., Mice Heterozygous for the Xanthine Oxidoreductase Gene Facilitate Lipid Accumulation in Adipocytes, Arterioscler Thromb Vasc Biol, 10.1161/ATVBAHA.113.302214, 34, 1, 44-51, 2014.01, OBJECTIVE: Xanthine oxidoreductase (XOR) catalyzes the production of uric acid with concomitant generation of reactive oxygen species. XOR has been shown to regulate adipogenesis through the control of peroxisome proliferator-activated receptor gamma, but its role in adipose tissue remains unclear. The aim of this study was to examine the role of XOR in adipose tissue using XOR genetically modified mice. APPROACH AND RESULTS: Experiments were performed using 2-, 4-, and 18-month-old XOR heterozygous mice (XOR+/-) and their wild-type littermates to evaluate the physiological role of XOR as the mice aged. Stromal vascular fraction cells were prepared from epididymal white adipose tissue in 2-month-old XOR mice to assess adipogenesis. At 18 months, XOR+/- mice had significantly higher body weight, higher systolic blood pressure, and higher incidence of insulin resistance compared with wild-type mice. At 4 months, blood glucose and the expressions of CCAAT enhancer-binding protein beta, peroxisome proliferator-activated receptor gamma, monocyte chemoattractant protein-1, and tumor necrosis factor alpha mRNA in epididymal white adipose tissue were significantly higher in XOR+/- than in wild-type mice. Furthermore, histological analysis of epididymal white adipose tissue in XOR+/- mice revealed that adipocyte size and the F4/80-positive macrophage count were increased. Experiments with a high-fat diet exhibited that body weight gain was also significantly higher in XOR+/- than in wild-type mice. In stromal vascular fraction cells derived from XOR+/- mice, the levels of peroxisome proliferator-activated receptor gamma, fatty acid-binding protein 4, and CCAAT enhancer-binding protein alpha mRNA were upregulated, and oxidative stress levels were elevated during differentiation into adipocytes. CONCLUSIONS: These results suggest that the reduction in XOR gene expression in mice augments lipid accumulation in adipocytes, accompanied by an increase in oxidative stress, and induces obesity with insulin resistance in older age..
41. Matsumoto, A., Yamafuji M., Tachibana, T., Nakabeppu, Y., Noda. M., Nakaya, H., Oral 'hydrogen water' induces neuroprotective ghrelin secretion in mice, Sci Rep, 10.1038/srep03273, 3, 3273, 2013.11, [URL], The therapeutic potential of molecular hydrogen (H(2)) is emerging in a number of human diseases and in their animal models, including in particular Parkinson's disease (PD). H(2) supplementation of drinking water has been shown to exert disease-modifying effects in PD patients and neuroprotective effects in experimental PD model mice. However, H(2) supplementation does not result in detectable changes in striatal H(2) levels, indicating an indirect effect. Here we show that H(2) supplementation increases gastric expression of mRNA encoding ghrelin, a growth hormone secretagogue, and ghrelin secretion, which are antagonized by the beta1-adrenoceptor blocker, atenolol. Strikingly, the neuroprotective effect of H(2) water was abolished by either administration of the ghrelin receptor-antagonist, D-Lys(3) GHRP-6, or atenolol. Thus, the neuroprotective effect of H(2) in PD is mediated by enhanced production of ghrelin. Our findings point to potential, novel strategies for ameliorating pathophysiology in which a protective effect of H(2) supplementation has been demonstrated..
42. Yasunari Sakai, Kazuhiro Ohkubo, Yuki Matsushita, Satoshi Akamine, Ishizaki Yoshito, Hiroyuki Torisu, Kenji Ihara, Masafumi Sanefuji, Min-Seon Kim, Ki-Up Lee, Chad A Shaw, Janghoo Lim, Yusaku Nakabeppu, Toshiro Hara, Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus., Eur J Med Genet, doi: 10.1016/j.ejmg.2013.06.009, 56, 9, 475-483, 2013.09, [URL], The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus..
43. Hideo Tsuji, Hiroko Ishii-Ohba, Tadahiro Shiomi, Naoko Shiomi, Takanori Katsube, Masahiko Mori, Mitsuru Nenoi, Ohno Mizuki, Daisuke Yoshimura, Sugako OKa, Yusaku Nakabeppu, Kouichi Tasumi, Masahiro Muto, Toshikiko Sada, Nature of nontargeted radiation effects observed during fractionated irradiation-induced thymic lymphomagenesis in mice, J Radiat Res, 10.1093/jrr/rrs128, 54, 3, 453-466, PMID: 23297316, 2013.05, Changes in the thymic microenvironment lead to radiation-induced thymic lymphomagenesis, but the phenomena are not fully understood. Here we show that radiation-induced chromosomal instability and bystander effects occur in thymocytes and are involved in lymphomagenesis in C57BL/6 mice that have been irradiated four times with 1.8-Gy gamma-rays. Reactive oxygen species (ROS) were generated in descendants of irradiated thymocytes during recovery from radiation-induced thymic atrophy. Concomitantly, descendants of irradiated thymocytes manifested DNA lesions as revealed by gamma-H2AX foci, chromosomal instability, aneuploidy with trisomy 15 and bystander effects on chromosomal aberration induction in co-cultured ROS-sensitive mutant cells, suggesting that the delayed generation of ROS is a primary cause of these phenomena. Abolishing the bystander effect of post-irradiation thymocytes by superoxide dismutase and catalase supports ROS involvement. Chromosomal instability in thymocytes resulted in the generation of abnormal cell clones bearing trisomy 15 and aberrant karyotypes in the thymus. The emergence of thymic lymphomas from the thymocyte population containing abnormal cell clones indicated that clones with trisomy 15 and altered karyotypes were prelymphoma cells with the potential to develop into thymic lymphomas. The oncogene Notch1 was rearranged after the prelymphoma cells were established. Thus, delayed nontargeted radiation effects drive thymic lymphomagenesis through the induction of characteristic changes in intrathymic immature T cells and the generation of prelymphoma cells..
44. Noriko Yutsudo, Takkashi Kamada, Kosuke Kajitani, Hiroko Nomaru, Atsuhisa Katogi, Yoko H Ohnishi, Yoshinori N Ohnisi, Kei-ichiro Takase, Hiroshu Shugeto, SAKUMI Kunihiko, Yusaku Nakabeppu, fosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior, Neuropsychopharmacology, doi:10.1038/npp.2012.260, 38, 5, 895-906, 2013.04, [URL], Patients with epilepsy are at high risk for major depression relative to the general population, and both disorders are associated with changes in adult hippocampal neurogenesis, although the mechanisms underlying disease onset remain unknown. The expression of fosB, an immediate early gene encoding FosB and ΔFosB/Δ2ΔFosB by alternative splicing and translation initiation, is known to be induced in neural progenitor cells within the subventricular zone of the lateral ventricles and subgranular zone of the hippocampus, following transient forebrain ischemia in the rat brain. Moreover, adenovirus-mediated expression of fosB gene products can promote neural stem cell proliferation. We recently found that fosB-null mice show increased depressive behavior, suggesting impaired neurogenesis in fosB-null mice. In the current study, we analyzed neurogenesis in the hippocampal dentate gyrus of fosB-null and fosBd/d mice that express ΔFosB/Δ2ΔFosB but not FosB, in comparison with wild-type mice, alongside neuropathology, behaviors and gene expression profiles. fosB-null but not fosBd/d mice displayed impaired neurogenesis in the adult hippocampus and spontaneous epilepsy. Microarray analysis revealed that genes related to neurogenesis, depression, and epilepsy were altered in the hippocampus of fosB-null mice. Thus, we conclude that the fosB-null mouse is the first animal model to provide a genetic and molecular basis for the comorbidity between depression and epilepsy with abnormal neurogenesis, all of which are caused by loss of a single gene, fosB..
45. Yukari Koga, Miyuki Inazato, Teruya Nakamura, Chie Hashikawa, Mami Chirifu, Asuka Michi, Taku Yamashita, Sachiko Toma, Akihiko Kuniyasu, Shinji Ikemizu, Yusaku Nakabeppu, Yuriko Yamagataa, Crystallization and preliminary X-ray analysis of human MTH1 with a homogeneous N-terminus, Acta Crystallogr Sect F Struct Biol Cryst Commun, 10.1107/S1744309112048002, 69, Pt1, 45-48, 2013.01, Human MTH1 (hMTH1) is an enzyme that hydrolyses several oxidized purine nucleoside triphosphates to their corresponding nucleoside monophosphates. Crystallographic studies have shown that the accurate mode of interaction between 8-oxoguanine and hMTH1 cannot be understood without determining the positions of the H atoms, as can be observed in neutron and/or ultrahigh-resolution X-ray diffraction studies. The hMTH1 protein prepared in the original expression system from Escherichia coli did not appear to be suitable for obtaining high-quality crystals because the hMTH1 protein had heterogeneous N-termini of Met1 and Gly2 that resulted from N-terminal Met excision by methionine aminopeptidase from the E. coli host. To obtain homogeneous hMTH1, the Gly at the second position was replaced by Lys. As a result, mutant hMTH1 protein [hMTH1(G2K)] with a homogeneous N-terminus could be prepared and high-quality crystals which diffracted to near 1.1 A resolution using synchrotron radiation were produced. The new crystals belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 46.36, b = 47.58, c = 123.89 A..
46. Shizuka Takaku, Hiroko Yanagisawa, Kazuhiko Watabe, Hidenori Horie, Toshihiko Kadoya, Kunihiko Sakumi, Yusaku Nakabeppu, Françoise Poirier, Kazunori Sango, GDNF promotes neurite outgrowth and upregulates galectin-1 through the RET/PI3K signaling in cultured adult rat dorsal root ganglion neurons, Neurochemistry International, 10.1016/j.neuint.2013.01.008, 62, 3, 330-339, 2013.01, Galectin-1 (GAL-1), a member of a family of β-galactoside binding animal lectins, is predominantly expressed in isolectin B4 (IB4)-binding small non-peptidergic (glial cell line-derived neurotrophic factor (GDNF)-responsive) sensory neurons in the sections of adult rat dorsal root ganglia (DRG), but its functional role and the regulatory mechanisms of its expression in the peripheral nervous system remain unclear. In the present study, both recombinant nerve growth factor (NGF) and GDNF (50 ng/ml) promoted neurite outgrowth from cultured adult rat DRG neurons, whereas GDNF, but not NGF, significantly increased the number of IB4-binding neurons and the relative protein expression of GAL-1 in the neuron-enriched culture of DRG. The GAL-1 expression in immortalized adult rat Schwann cells IFRS1 and DRG neuron-IFRS1 cocultures was unaltered by treatment with GDNF, which suggests that GDNF/GAL-1 signaling axis is more related to neurite outgrowth, rather than neuron-Schwann cell interactions. The GDNF-induced neurite outgrowth and GAL-1 upregulation were attenuated by anti-GDNF family receptor (RET) antibody and phosphatidyl inositol-3’-phosphate-kinase (PI3K) inhibitor LY294002, suggesting that the neurite-outgrowth promoting activity of GDNF may be attributable, at least partially, to the upregulation of GAL-1 through RET-PI3K pathway. On the contrary, no significant differences were observed between GAL-1 knockout and wild-type mice in DRG neurite outgrowth in the presence or absence of GDNF. Considerable immunohistochemical colocalization of GAL-3 with GAL-1 in DRG sections and GDNF-induced upregulation of GAL-3 in cultured DRG neurons imply the functional redundancy between these galectins..
47. Harini Sampath, Vladimir Vartanian, M. Rick Rollins, Kunihiko Sakumi, Yusaku Nakabeppu, R. Stephen Lloyd, 8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Increases Susceptibility to Obesity and Metabolic Dysfunction, PLoS ONE, 10.1371/journal.pone.0051697, 7, 12, e51697, 2012.12, [URL], Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase (OGG1). While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient (Ogg1(-/-)) mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet (HFD), compared to wild-type (WT) animals. Ogg1(-/-) animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1(-/-) mice have a higher resting VCO(2) and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1alpha were significantly downregulated in Ogg1(-/-) livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1(-/-) mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1(-/-) mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1(-/-) mice..
48. Zijing Sheng, Sugako Oka, Daisuke Tsuchimoto, Abolhassani Nona, Nomaru Hiroko, Kunihiko Sakumi, Yamada Hidetaka, Yusaku Nakabeppu, 8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair, J Clin Invest, 10.1172/JCI65053, 122, 12, 4344-4361, 2012.12, [URL], 8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG–paired adenine. Mutant mice lacking 8-oxo–2′-deoxyguanosine triphosphate–depleting (8-oxo–dGTP–depleting) MTH1 and/or 8-oxoG–excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress..
49. Yogianti F, Kunisada M, Ono R, Sakumi K, Nakabeppu Y, Nishigori C., Skin tumours induced by narrowband UVB have higher frequency of p53 mutations than tumours induced by broadband UVB independent of Ogg1 genotype, Mutagenesis, doi: 10.1093/mutage/ges029., 27, 6, 637-643, 2012.11.
50. Murakami Y, Ikeda Y, Yoshida N, Notomi S, Hisatomi T, Oka S, De Luca G, Yonemitsu Y, Bignami M, Nakabeppu Y, Ishibashi T., MutT Homolog-1 Attenuates Oxidative DNA Damage and Delays Photoreceptor Cell Death in Inherited Retinal Degeneration, Am J Pathol, doi: 10.1016/j.ajpath.2012.06.026, 181, 4, 1378-1386, 2012.10.
51. Nishimura Y, Takiguchi S, Yoshioka K, Nakabeppu Y, Itoh K., Silencing of SNX1 by siRNA stimulates the ligand-induced endocytosis of EGFR and increases EGFR phosphorylation in gefitinib-resistant human lung cancer cell lines, Int J Oncol, doi: 10.3892/ijo.2012.1578, 2012.06, Gefitinib is known to suppress the activation of EGFR signaling, which is required for cell survival and proliferation in non-small cell lung cancer (NSCLC) cell lines. We previously demonstrated that the gefitinib-sensitive NSCLC cell line PC9 shows efficient ligand-induced endocytosis of phosphorylated EGFR (pEGFR). In contrast, the gefitinib-resistant NSCLC cell lines QG56 and A549 showed internalized pEGFR accumulation in the aggregated early endosomes, and this was associated with SNX1, a protein that interacts with and enhances the degradation of EGFR upon EGF stimulation. In the present study, to investigate the role of SNX1 on EGF-stimulated EGFR/pEGFR endocytosis via the endocytic pathway, we examined the effect of depletion of SNX1 expression by siRNA in human NSCLC cell lines. Using immunofluorescence, we demonstrated that transfection of SNX1 siRNA into gefitinib-resistant NSCLC cells resulted in the disappearance of a large amounts of SNX1 staining. In addition, upon 15 min of EGF stimulation, we observed an efficient EGFR phosphorylation and a rapid endocytic delivery of pEGFR from early endosomes to late endosomes. Further, western blot analysis revealed that silencing of SNX1 expression by siRNA in the gefitinib-resistant cells leads to an accelerated degradation of EGFR along with a dramatic increase in the amounts of pEGFR after EGF stimulation. Based on these findings, we suggest that SNX1 is involved in the negative regulation of ligand-induced EGFR phosphorylation and mediates EGFR/pEGFR trafficking out of early endosomes for targeting to late endosomes/lysosomes via the early/late endocytic pathway in human lung cancer cells..
52. Kunisada M, Yogianti F, Sakumi K, Ono R, Nakabeppu Y, Nishigori C , Increased Expression of Versican in the Inflammatory Response to UVB- and Reactive Oxygen Species-Induced Skin Tumorigenesis, Am J Pathol, 179, 6, 3056-3065, 2011.12.
53. Ohnishi YN, Ohnishi YH, Hokama M, Nomaru H, Yamazaki K, Tominaga Y, Sakumi K, Nestler EJ, Nakabeppu Y, FosB is essential for the enhancement of stress tolerance and antagonizes locomotor sensitization by ΔFosB, Biological Psychiatry, 186, 4, 1943-1950, 2011.09, BACKGROUND:
Molecular mechanisms underlying stress tolerance and vulnerability are incompletely understood. The fosB gene is an attractive candidate for regulating stress responses, because ΔFosB, an alternative splice product of the fosB gene, accumulates after repeated stress or antidepressant treatments. On the other hand, FosB, the other alternative splice product of the fosB gene, expresses more transiently than ΔFosB but exerts higher transcriptional activity. However, the functional differences of these two fosB products remain unclear.

METHODS:
We established various mouse lines carrying three different types of fosB allele, wild-type (fosB(+)), fosB-null (fosB(G)), and fosB(d) allele, which encodes ΔFosB but not FosB, and analyzed them in stress-related behavioral tests.

RESULTS:
Because fosB(+/d) mice show enhanced ΔFosB levels in the presence of FosB and fosB(d/d) mice show more enhanced ΔFosB levels in the absence of FosB, the function of FosB can be inferred from differences observed between these lines. The fosB(+/d) and fosB(d/d) mice showed increased locomotor activity and elevated Akt phosphorylation, whereas only fosB(+/d) mice showed antidepressive-like behaviors and increased E-cadherin expression in striatum compared with wild-type mice. In contrast, fosB-null mice showed increased depression-like behavior and lower E-cadherin expression.

CONCLUSIONS:
These findings indicate that FosB is essential for stress tolerance mediated by ΔFosB. These data suggest that fosB gene products have a potential to regulate mood disorder-related behaviors..
54. Iwama E, Tsuchimoto D, Iyama T, Sakumi K, Nakagawara A, Takayama K, Nakanishi Y, Nakabeppu Y., Cancer-Related PRUNE2 Protein Is Associated with Nucleotides and Is Highly Expressed in Mature Nerve Tissues, J Mol Neurosci, 10.1007/s12031-010-9490-2, 44, 2, 103-114, 2011.06, [URL].
55. Nishimura Y, Yoshioka K, Takiguchi S, Bereczky B, Nakabeppu Y, Itoh K, A Role for SNX1 in the Regulation of EGF-Dependent Phosphorylated EGFR Endocytosis Via the Early/Late Endocytic Pathway in a Gefitinib- Sensitive Human Lung Cancer Cells, Current Signal Transduction Therapy, 6, 3, 383-395, 2011.06.
56. Guikema JE, Gerstein RM, Linehan EK, Evan-Browning E, Tsuchimoto D, Nakabeppu Y, Schrader CE, Apurinic/Apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge, J Immunol, 186, 4, 1943-1950, 2011.02.
57. Goto M, Shinmura K, Nakabeppu Y, Tao H, Yamada H, Tsuneyoshi T, Sugimura H., Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer, Hum Mutat, 31, 11, E1861-1874., 2010.11.
58. Iyama T, Abolhassani N, Tsuchimoto D, Nonaka M, Nakabeppu Y., NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest, Nucleic Acids Research, 38, 14, 4834-4843, 2010.06, 活性酸素等による化学修飾を受けたヌクレオチドはヌクレオチドプールから取り除かれなければ細胞に対して毒性を示す.我々は,ATPの脱アミノ化で生じるイノシン三リン酸 (ITP)に結合するタンパクとして,ヒトNUDT16タンパクを同定した組み換えNUDT16タンパクはイノシン二リン酸 (IDP)とデオキシイノシン二リン酸 (dIDP)に対して最も高いkcat/Km 値を示し,効率よく分解した.NUDT16はITP/dITPも分解し,大部分が核内,特に核小体内に局在していた.培養ヒト細胞でNUDT16をノックダウンすると,S期での細胞周期遅延、細胞増殖の低下、核DNAの一本鎖切断の蓄積の増加,さらにRNAへのイノシンの蓄積が引き起こされた.以上より,NUDT16がIDP/dIDP分解酵素であり,ITPとdITPの悪影響から細胞を守るために主に核内で機能することを明らかにした..
59. Abolhassani, N, Iyama, T, Tsuchimoto, D, Sakumi, K, Ohno, M, Behmanesh, M, Nakabeppu, Y., NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals, Nucleic Acids Research, 38, 9, 2891-2903, 2010.05.
60. Martin SA, McCabe N, Mullarkey M, Cummins R, Burgess DJ, Nakabeppu Y, Oka S, Kay E, Lord CJ, Ashworth A. , DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1, Cancer Cell, 17, 3, 1235-1248, 2010.03.
61. Behmanesh, M., Sakumi, K., Abolhassani, N., Toyokuni, S., Oka, S., Ohnishi, Y., Tsuchimoto, D., and Nakabeppu, Y. , ITPase-deficient mice show growth retardation and die before weaning, Cell Death Differ, 16, 10, 1315-1322, 2009.10.
62. Gushima M, Hirahashi M, Matsumoto T, Fujita K, Fujisawa R, Mizumoto K, Nakabeppu Y, Iida M, Yao T, Tsuneyoshi M., Altered expression of MUTYH and an increase in 8-hydroxydeoxyguanosine are early events in ulcerative colitis-associated carcinogenesis, J Pathol, 219, 1, 77-86, 2009.09.
63. Kyota Fujita, Toshihiro Seike, Noriko Yutsudo, Mizuki Ohno, Hidetaka Yamada, Hiroo Yamaguchi, Kunihiko Sakumi, Yukiko Yamakawa, Mizuho A. Kido, Atsushi Takaki, Toshihiko Katafuchi, Yoshinori Tanaka, Yusaku Nakabeppu, Mami Noda , Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson’s Disease, PLoS ONE, 4, 9, e7247, 2009.09.
64. Sabouri Z, Okazaki IM, Shinkura R, Begum N, Nagaoka H, Tsuchimoto D, Nakabeppu Y, Honjo T., Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobulin genes, Int Immunol, 21, 8, 947-955, 2009.08.
65. Kajitani, K., Nomaru, H., Ifuku, M., Yutsudo, N., Dan, Y., Miura, T., Tsuchimoto, D., Sakumi, K., Kadoya, T., Horie, H., Poirier, F., Noda, M. and Nakabeppu, Y., Galectin-1 promotes basal and kainate-induced proliferation of neural progenitors in the dentate gyrus of adult mouse hippocampus, Cell Death Differ, 16, 3, 417-427, 2009.03.
66. Nonaka, M., Tsuchimoto, D., Sakumi, K. and Nakabeppu, Y., Mouse RS21-C6 is a mammalian 2’-deoxycytidine 5’-triphosphate pyrophosphohydrolase, preferring 5-iodocytosine, FEBS J, 276, 6, 1654-1666, 2009.03.
67. Nakane, H., Hirota, S., Brooks, P. J., Nakabeppu, Y., Nakatsu, Y., Nishimune, Y., Iino, A., and Tanaka, K. , Impaired spermatogenesis and elevated spontaneous tumorigenesis in xeroderma pigmentosum group A gene (Xpa)-deficient mice. , DNA Repair, 7, 12, 1938-1950, 2008.12.
68. Ohnishi YN, Sakumi K, Yamazaki K, Ohnishi YH, Miura T, Tominaga Y, Nakabeppu Y., Antagonistic regulation of cell-matrix adhesion by FosB and ΔFosB/Δ2ΔFosB encoded by alternatively spliced forms of fosB transcripts., Mol Biol Cell, 19(11): 4717-4729, 2008.11.
69. De Luca, G., Russo, M.T., Degan, P., Tiveron, C., Zijno, A., Meccia, E., Ventura, I., Mattei, E., Nakabeppu, Y., Crescenzi, M., Pèpponi, R., Pzzola, A., Popoli, P. and Bignami, M., A Role for Oxidized DNA Precursors in Huntington's Disease-Like Striatal Neurodegeneration, PLoS Genet, 4, 11, e1000266, 2008.11.
70. Dan Y, Ohta Y, Tsuchimoto D, Ohno M, Ide Y, Sami M, Kanda T, Sakumi K, Nakabeppu Y., Altered gene expression profiles and higher frequency of spontaneous DNA strand breaks in APEX2-null thymus., DNA Repair, 7 (9): 1437-1454, 2008.09.
71. Yamamoto, S., Tanaka, K., Sakimura, R., Okada, T., Nakamura, T., Li, Y., Takasaki, M., Nakabeppu, Y., and Iwamoto, Y. , Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in Chondrosarcoma cell lines, Anticancer Research, 28: 1585-1592, 2008.07.
72. Yanaru-Fujisawa R, Matsumoto T, Ushijima Y, Esaki M, Hirahashi M, Gushima M, Yao T, Nakabeppu Y, Iida M., Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis., Clin Genet, 73(6):545-553, 2008.06.
73. Ichikawa J, Tsuchimoto D, Oka S, Ohno M, Furuichi M, Sakumi K, Nakabeppu Y., Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death., DNA Repair, 7(3):418-430, 2008.03.
74. Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y., Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs., EMBO Journal., 27(2):421-432., 2008.01.
75. Kunisada M, Kumimoto H, Ishizaki K, Sakumi K, Nakabeppu Y, Nishigori C., Narrow-band UVB induces more carcinogenic skin tumors than broad-band UVB through the formation of cyclobutane pyrimidine dimer., The Journal of Investigative Dermatology, 127(12):2865-2871., 2007.12.
76. Guikema JE, Linehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, Stavnezer J, Schrader CE., APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination., Journal of Experimental Medicine, 204(12):3017-3026, 2007.11.
77. Sakamoto K, Tominaga Y, Yamauchi K, Nakatsu Y, Sakumi K, Yoshiyama K, Egashira A, Kura S, Yao T, Tsuneyoshi M, Maki H, Nakabeppu Y, Tsuzuki T., MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis., Cancer Research, 67(14):6599-6604. , 2007.07.
78. Kuraoka I, Suzuki K, Ito S, Hayashida M, Kwei JS, Ikegami T, Handa H, Nakabeppu Y, Tanaka K., RNA polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFIIS., DNA Repair, 6, 6, 841-851, 2007.06.
79. Ohtsubo T, Ohya Y, Nakamura Y, Kansui Y, Furuichi M, Matsumura K, Fujii K, Iida M, Nakabeppu Y., Accumulation of 8-oxo-deoxyguanosine in cardiovascular tissues with the development of hypertension., DNA Repair, 6, 6, 760-769, 2007.06.
80. Miyata K, Yasukawa T, Fukuda M, Takeuchi T, Yamazaki K, Sakumi K, Tamamori-Adachi M, Ohnishi Y, Ohtsuki Y, Nakabeppu Y, Kitajima S, Onishi S, Aso T., Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A., Cell Death Differ, 14(4):716-726, 2007.04.
81. Nakamura T, Kitaguchi Y, Miyazawa M, Kamiya H, Toma S, Ikemizu S, Shirakawa M, Nakabeppu Y, Yamagata Y., Crystallization and preliminary X-ray analysis of human MTH1 complexed with two oxidized nucleotides, 8-oxo-dGMP and 2-oxo-dATP., Acta Crystallograph Sect F Struct Biol Cryst Commun., 62(Pt 12):1283-1285, 2006.12.
82. Kamiya H, Cadena-Amaro C, Dugue L, Yakushiji H, Minakawa N, Matsuda A, Pochet S, Nakabeppu Y, Harashima H., Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein., J. Biochem., 140(6):843-849, 2006.12.
83. Arima T, Yamasaki K, John RM, Kato K, Sakumi K, Nakabeppu Y, Wake N, Kono T., The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice., Genomics., 88(5):650-658, 2006.11.
84. Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S, Verhofstad N, Nakabeppu Y, Baum LG, Bakkers J, Mayo KH, Poirier F, Griffioen AW., Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy., Proc Natl Acad Sci U S A., 103(43):15975-15980, 2006.10.
85. Akatsuka S, Aung TT, Dutta KK, Jiang L, Lee WH, Liu YT, Onuki J, Shirase T, Yamasaki K, Ochi H, Naito Y, Yoshikawa T, Kasai H, Tominaga Y, Sakumi K, Nakabeppu Y, Kawai Y, Uchida K, Yamasaki A, Tsuruyama T, Yamada Y, Toyokuni S., Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis., Am. J. Pathol., 169(4):1328-1342, 2006.10.
86. Arai T, Fukae J, Hatano T, Kubo S, Ohtsubo T, Nakabeppu Y, Mori H, Mizuno Y, Hattori N., Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease., Acta Neuropathol, 112(2):139-145., 2006.08.
87. Sakai Y, Oda H, Yoshimura D, Furuichi M, Kang D, Iwai S, Hara T, Nakabeppu Y., The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal., J. Mol. Med., 4(8):660-670, 2006.08.
88. Arima, H., Kiyohara Y., Tanizaki Y., Nakabeppu Y., Kubo M., Kato I., Sueishi K., Tsuneyoshi M., Fujishima M. and Iida M, Angiotensin I-converting enzyme gene polymorphism modifies the smoking-cancer association: the Hisayama Study., Europ. J. Cancer Prev., 5(3):196-201, 2006.06.
89. Ohno M, Miura T, Furuichi M, Tominaga Y, Tsuchimoto D, Sakumi K, Nakabeppu Y., A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome., Genome Res., 6(5):567-575, 2006.05.
90. Powell, K. J., Binder T. L., Hori S., Nakabeppu Y., R. D., Weinberger, Lipska B. K. and Robertson G. S., Neonatal Ventral Hippocampal Lesions Produce an Elevation ofΔFosB-like Protein(s) In the Rodent Neocortex., Neuropsychopharmacol., 31(4):700-711, 2006.04.
91. Yamaguchi, H., Kajitani K., Dan Y., Furuichi M., Ohno M., Sakumi K., Kang D. and Nakabeppu Y., MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine., Cell Death Differ, 13(4):551-563, 2006.04.
92. Nakamura TY, Jeromin A, Smith G, Kurushima H, Koga H, Nakabeppu Y, Wakabayashi S, Nabekura J., Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons., J. Cell Biol., 172(7):1081-1091, 2006.03.
93. Kajitani, K., Yamaguchi H., Dan Y., Furuichi M., Kang D. and Nakabeppu Y., MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity., J. Neurosci., 26(6):1688-1698, 2006.02.
94. Torisu, K., Tsuchimoto D., Ohnishi Y. and Nakabeppu Y., Hematopoietic tissue-specific expression of mouse Neil3 for endonuclease VIII-like protein., J. Biochem., 10.1093/jb/mvi168, 138, 6, 763-772, 138(6):763-772, 2005.12.
95. Sato, T., Hidaka K., Iwanaga A., Ito M., Asano M., Nakabeppu Y., Morisaki T. and Yoshioka K., Impairment of cardiomyogenesis in embryonic stem cells lacking scaffold protein JSAP1., Biochem. Biophys. Res. Commun., 10.1016/j.bbrc.2005.10.052, 338, 2, 1152-1157, 338 (2):1152-1157., 2005.12.
96. Wei, P., Taniguchi S., Sakai Y., Imamura M., Inoguchi T., Nawata H., Oda S., Nakabeppu Y., Nishimura J. and Ikuyama S., Expression of adipose differentiation-related protein (ADRP) is conjointly regulated by PU.1 and AP-1 in macrophages., J. Biochem., 10.1093/jb/mvi136, 138, 4, 399-412, 138 (4):399-412., 2005.10.
97. Kurushima, H., Ohno M., Miura T., Nakamura T. Y., Horie H., Kadoya T., Ooboshi H., Kitazono T., Ibayashi S., Iida M. and Nakabeppu Y., Selective induction of ΔFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of ΔFosB and galectin-1 in neuroprotection and neurogenesis., Cell Death Differ, 10.1038/sj.cdd.4401648, 12, 8, 1078-1096, 12 (8):1078-1096., 2005.08.
98. Kunisada, M., Sakumi K., Tominaga Y., Budiyanto A., Ueda M., Ichihashi M., Nakabeppu Y. and Nishigori C., 8-Oxoguanine Formation Induced by Chronic UVB Exposure Makes Ogg1 Knockout Mice Susceptible to Skin Carcinogenesis., Cancer Res, 10.1158/0008-5472.CAN-05-0724, 65, 14, 6006-6010, 65 (14):6006-10., 2005.07.
99. Campalans, A., Marsin S., Nakabeppu Y., O'Connor T R., Boiteux S. and Radicella J. P., XRCC1 interactions with multiple DNA glycosylases: A model for its recruitment to base excision repair., DNA Repair, 10.1016/j.dnarep.2005.04.014, 4, 7, 826-835, 4 (7):826-35., 2005.07.
100. Tamura, K., Hua B., Adachi S., Guney I., Kawauchi J., Morioka M., Tamamori-Adachi M., Tanaka Y., Nakabeppu Y., Sunamori M., Sedivy J. M. and Kitajima S., Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation., EMBO J, 10.1038/sj.emboj.7600742, 24, 14, 2590-2601, 24 2590-2601, 2005.06.
101. Fukae, J., Takanashi M., Kubo S.-i., Nishioka K.-i., Nakabeppu Y., Mori H., Mizuno Y. and Hattori N., Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson's disease and related neurodegenerative disorders., Acta Neurophathologica, 10.1007/s00401-004-0937-9, 109, 3, 256-262, 109 (3):256-262., 2005.03.
102. Behmanesh, M., Sakumi K., Tsuchimoto D., Torisu K., Ohnishi-Honda Y., Derrick E R. and Nakabeppu Y., Characterization of the structure and expression of mouse Itpa gene and its related sequences in the mouse genome., DNA Research, 10.1093/dnares/12.1.39, 12, 1, 39-51, 12 (1):29-41., 2005.02.
103. Furuya, H., Shinnoh N., Ohyagi Y., Ikezoe K., Kikuchi H., Osoegawa M., Fukumaki Y., Nakabeppu Y., Hayashi T., Kira J.-i. and Abe M., Some flavonoids and DHEA-S prevent the cis-effect of expanded CTG repeats in a stable PC12 cell transformant., Biochemical Pharmacology, 10.1016/j.bcp.2004.10.005, 69, 3, 503-516, 69 (3):503-516., 2005.02.
104. Ushijima, Y., Y. Tominaga, T. Miura, Daisuke Tsuchimoto, K. Sakumi, and Y. Nakabeppu., A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA., Nucleic Acids Res., 10.1093/nar/gki214, 33, 2, 672-682, 33(2):672-682., 2005.01.
105. Robertson, G. S., C. J. Lee, K. Sridhar, Y. Nakabeppu, M. Cheng, Y.-M. Wang, and M. G. Caron., Clozapine-, but not haloperidol-, induced increases in deltaFosB-like immunoreactivity is completely blocked in the striatum of mice lacking D3 dopamine receptors, Eur. J. Neurosci., 10.1111/j.1460-9568.2004.03774.x, 20, 11, 3189-3194, 20(11):3189-3194., 2004.12.
106. Ide, Y., Tsuchimoto, D., Tominaga, Y., Nakashima, M., Watanabe, T., Sakumi, K., Ohno, M. and Nakabeppu, Y., Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice., Blood, 10.1182/blood-2004-04-1476, 104, 13, 4097-4103, 104(13):4097-4103, 2004.12.
107. Keiji Hashimoto, Yusaku Nakabeppu, Masaaki Moriya, Futile short-patch DNA base excision repair of adenine:8-oxoguanine mispair, Nucleic Acids Res., 10.1093/nar/gkh909, 32, 19, 5928-5934, 32(19):5928-5234, 2004.11.
108. Nunoshiba, T., R. Ishida, S. Sasaki, S. Iwai, Nakabeppu, Y. and Yamamoto, K., A novel Nudix hydrolase for oxidized purine nucleoside triphosphates encoded by ORFYLR151c ( PCD1 gene) in Saccharomyces cerevisiae, Nucelic Acids Res., 10.1093/nar/gkh868, 32, 18, 5339-5348, 32(18):5339-5348, 2004.10.
109. T. Miura, M. Takahashi, H. Horie, H. Kurushima, D. Tsuchimoto, K. Sakumi, Y. Nakabeppu, Galectin-1beta, a natural monomeric form of galectin-1 lacking its six amino-terminal residues promotes axonal regeneration but not cell death., Cell Death and Differentiation, 10.1038/sj.cdd.4401462, 11, 10, 1076-1083, 11(10):1076-1083, 2004.10.
110. Masaki Mishima, Yasunari Sakai, Noriyuki Itoh, Hiroyuki Kamiya, Masato Furuichi, Masayuki Takahashi, Yuriko Yamagata, Shigenori Iwai, Yusaku Nakabeppu, Masahiro Shirakawa, Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates., J. Biol. Chem., 10.1074/jbc.M402393200, 279, 32, 33806-33815, 279(32):33806-33815, 2004.08.
111. Yohei Tominaga, Yasuhiro Ushijima, Daisuke Tsuchimoto, Masaki Mishima, Masahiro Shirakawa, Seiki Hirano, Kunihiko Sakumi, Yusaku Nakabeppu., MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain., Nucleic Acids Res., 10.1093/nar/gkh642, 32, 10, 3198-3211, 32 (10):3198-3211, 2004.06.
112. Kimura, Y., S. Oda, A. Egashira, Y. Kakeji, H. Baba, Y. Nakabeppu, and Y. Maehara., A variant form of hMTH1, a human homologue of mutT E. coli mutator gene, correlates with somatic mutation in p53 tumour suppressor gene in gastric cancer patients., J. Med. Genet., 10.1136/jmg.2003.013268, 41, 5, 41 (5): e57, 2004.05.
113. Iida, T., Furuta, A., Nakabeppu, Y., and Iwaki, T., Defense mechanism to oxidative DNA damage in glial cells., Neuropathol., 10.1111/j.1440-1789.2003.00540.x, 24, 2, 125-130, 24 (2): 125-130, 2004.05.
114. Kamiya, H., H. Yakushiji, L. Dugue, M. Tanimoto, S. Pochet, Y. Nakabeppu, H. Harashima., Probing the substrate recognition mechanism of the human MTH1 protein by nucleotide analogs., J. Mol. Biol., 10.1016/j.jmb.2003.12.060, 336, 4, 843-850, 336 (4): 843-850, 2004.02.
115. Ichinoe, A., M. Behmanesh, Y. Tominaga, Y. Ushijima, S. Hirano, Y. Sakai, D. Tsuchimoto, K. Sakumi, N. Wake, Y. Nakabeppu., Identification and characterization of two forms of mouse MUTYH proteins encoded by alternatively spliced transcripts., Nucleic Acids Res., 10.1093/nar/gkh214, 32, 2, 477-487, 32(2):477-487, 2004.01.
116. Russo, M. T., M. F. Blasi, F. Chiera, P. Fortini, P. Degan, P. Macpherson, M. Furuichi, Y. Nakabeppu, P. Karran, G. Aquilina, and M. Bignami., The oxidized Deoxynucleotide Triphosphate Pool is a Significant Contributor to Genetic Instability in Mismatch Repair-Deficient Cells., Mol. Cell Biol., 10.1128/MCB.24.1.465-474.2004, 24, 1, 465-474, 24: 465-474., 2004.01.
117. Nakagawachi, T., H. Soejima, Z. Wei, T. Urano, S. Matsukura, K. Higashimoto, Y. Satoh, Y. Kitajima, H. Harada, K. Furukawa, H. Matsuzaki, M. Emi, K. Miyazaki, Y. Nakabeppu, M. Sekiguchi, and T. Mukai., Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer., Oncogene, 10.1038/sj.onc.1207183, 22, 55, 8835-8844, 22:8835-8844, 2003.12.
118. Xu, P., K. Yoshioka, D. Yoshimura, Y. Tominaga, T. Nishioka, M. Ito, and Y. Nakabeppu., In vitro development of mouse embryonic stem cells lacking JSAP1 scaffold protein revealed its requirement during early embryonic neurogenesis., J. Biol. Chem., 10.1074/jbc.M307888200, 278, 48, 48422-48433, 278:48422-48433, 2003.11.
119. Hirano, S., Y. Tominaga, A. Ichinoe, Y. Ushijima, D. Tsuchimoto, Y. Honda-Ohnishi, T. Ohtsubo, K. Sakumi, and Y. Nakabeppu., Mutator phenotype of MUTYH-null mouse embryonic stem cells., J. Biol. Chem., 10.1074/jbc.C300316200, 278, 40, 38121-38124, 278:38121-38124, 2003.10.
120. Yoshimura, D., K. Sakumi, M. Ohno, Y. Sakai, M. Furuichi, S. Iwai, and Y. Nakabeppu., An oxidized purine nucleoside triphosphatase, MTH1 suppresses cell death caused by oxidative stress., J. Biol. Chem., 278:37965-37973, 2003.09.
121. Yuan, Q., K. Matsumoto, Y. Nakabeppu, and T. Iwaki., A comparative immunohistochemistry of O6-methylguanine-DNA methyltransferase and p53 in diffusely infiltrating astrocytomas., Neuropathol., 10.1046/j.1440-1789.2003.00504.x, 23, 3, 203-209, 23:203-209, 2003.09.
122. Tahara, K., D. Tsuchimoto, Y. Tominaga, S. Asoh, S. Ohta, M. Kitagawa, H. Horie, T. Kadoya, and Y. Nakabeppu., ΔFosB but not FosB Induces Delayed Apoptosis Independent of Cell Proliferation in the Rat1a Embryo Cell Line., Cell Death Diff., 10.1038/sj.cdd.4401173, 10, 5, 496-507, 10:496-507, 2003.04.
123. Yamazaki, K., T. Aso, Y. Ohnishi, M. Ohno, K. Tamura, T. Shuin, S. Kitajima, and Y. Nakabeppu., Mammalian elongin A is not essential for cell viability but required for proper cell-cycle progression with limited alteration of gene expression., J. Biol. Chem., 10.1074/jbc.C300047200, 278, 15, 13585-13589, 278:13585-13589, 2003.04.
124. Sakumi, K., Y. Tominaga, M. Furuichi, P. Xu, T. Tsuzuki, M. Sekiguchi, and Y. Nakabeppu., Ogg1 Knockout-associated Lung Tumorigenesis and Its Suppression by Mth1 Gene Disruption., Cancer Res., 63, 5, 902-905, 63:902-905, 2003.03.
125. Matsukura, S., H. Soejima, T. Nakagawachi, H. Yakushiji, A. Ogawa, M. Fukuhara, K. Miyazaki, Y. Nakabeppu, M. Sekiguchi, and T. Mukai., CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection., Br. J. Cancer, 10.1038/sj.bjc.6600743, 88, 4, 521-529, 88:521-529, 2003.02.
126. Tsuruya, K., M. Furuichi, Y. Tominaga, M. Shinozaki, M. Tokumoto, T. Yoshimitsu, K. Fukuda, H. Kanai, H. Hirakata, M. Iida, and Y. Nakabeppu., Accumulation of 8-oxoguanine in the cellular DNA and the alteration of the OGG1 expression during ischemia-reperfusion injury in the rat kidney., DNA Repair, 10.1016/S1568-7864(02)00214-8, 2, 2, 211-229, 2:211-229, 2003.02.
127. Ide, Y., D. Tsuchimoto, Y. Tominaga, Y. Iwamoto, and Y. Nakabeppu., Characterization of the genomic structure and expression of the mouse Apex2 gene., Genomics, 10.1016/S0888-7543(02)00009-5, 81, 1, 47-57, 81:47-57, 2003.01.
128. Arima, H., Y. Kiyohara, Y. Tanizaki, Y. Nakabeppu, M. Kubo, I. Kato, K. Sueishi, M. Tsuneyoshi, M. Fujishima, and M. Iida., Detection of angiotensin-converting enzyme gene insertion/deletion polymorphism from paraffin-embedded tissues: the Hisayama study., Circ. J., 10.1253/circj.66.1034, 66, 11, 1034-1036, 66:1034-1036, 2002.11.
129. Zhang, D., L. Zhang, D. W. Lou, Y. Nakabeppu, J. Zhang, and M. Xu, The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression., J. Neurochem., 10.1046/j.1471-4159.2002.01089.x, 82, 6, 1453-1464, 82:1453-1464, 2002.09.
130. Yamazaki, K., L. Guo, K. Sugahara, C. Zhang, H. Enzan, Y. Nakabeppu, S. Kitajima, and T. Aso., Identification and biochemical characterization of a novel transcription elongation factor elongin A3., J. Biol. Chem., 10.1074/jbc.M202859200, 277, 29, 26444-26451, 277:26444-26451, 2002.06.
131. Nunoshiba, T., T. Watanabe, Y. Nakabeppu, and K. Yamamotoa., Mutagenic target for hydroxyl radicals generated in Escherichia coli mutant deficient in Mn- and Fe-superoxide dismutases and Fur, a repressor for iron-uptake systems., DNA Repair, 10.1016/S1568-7864(02)00014-9, 1, 5, 411-418, 1:411-418, 2002.05.
132. Takahashi, M., F. Maraboeuf, Y. Sakai, H. Yakushiji, M. Mishima, M. Shirakawa, S. Iwai, H. Hayakawa, M. Sekiguchi, and Y. Nakabeppu., Role of tryptophan residues in the recognition of mutagenic oxidized nucleotides by human antimutator MTH1 protein., J. Mol. Biol., 10.1016/S0022-2836(02)00163-8, 319, 1, 129-139, 319:129-139, 2002.05.
133. Kohya, N., K. Miyazaki, S. Matsukura, H. Yakushiji, Y. Kitajima, K. Kitahara, M. Fukuhara, Y. Nakabeppu, and M. Sekiguchi., Deficient Expression of O(6)-Methylguanine-DNA Methyltransferase Combined With Mismatch-Repair Proteins hMLH1 and hMSH2 Is Related to Poor Prognosis in Human Biliary Tract Carcinoma., Ann. Surg. Oncol., 10.1245/aso.2002.9.4.371, 9, 4, 371-379, 9:371-379, 2002.05.
134. Nishioka, T., K. Sakumi, T. Miura, K. Tahara, H. Horie, T. Kadoya, and Y. Nakabeppu., fosB gene products trigger cell proliferation and morphological alteration with an increased expression of a novel processed form of galectin-1 in the rat 3Y1 embryo cell line., J. Biochem., 131, 5, 653-661, 131:653-661, 2002.05.
135. Kikuchi, H., A. Furuta, K. Nishioka, S. O. Suzuki, Y. Nakabeppu, and T. Iwaki., Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis., Acta Neuropathol., 10.1007/s00404-001-0480-x, 103, 4, 408-414, 103:408-414, 2002.04.
136. Kato, K., S. Horiuchi, A. Takahashi, Y. Ueoka, T. Arima, T. Matsuda, H. Kato, J. Nishida Ji, Y. Nakabeppu, and N. Wake., Contribution of Estrogen Receptor alpha to Oncogenic K-Ras-mediated NIH3T3 Cell Transformation and Its Implication for Escape from Senescence by Modulating the p53 Pathway., J. Biol. Chem., 10.1074/jbc.M107391200, 277, 13, 11217-11224, 277:11217-11224, 2002.03.
137. Sakai, Y., M. Furuichi, M. Takahashi, M. Mishima, S. Iwai, M. Shirakawa, and Y. Nakabeppu., A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-Oxo-dGTP by human MTH1., J. Biol. Chem., 10.1074/jbc.M110566200, 277, 10, 8579-8587, 277:8579-8587, 2002.03.
138. Hayashi, H., Y. Tominaga, S. Hirano, A. E. McKenna, Y. Nakabeppu, and Y. Matsumoto., Replication-Associated Repair of Adenine:8-Oxoguanine Mispairs by MYH., Current Biol., 10.1016/S0960-9822(02)00686-3, 12, 4, 335-339, 12:335-339, 2002.02.
139. Fujikawa, K., H. Yakushiji, Y. Nakabeppu, T. Suzuki, M. Masuda, H. Ohshima, and H. Kasai., 8-Chloro-dGTP, a hypochlorous acid-modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog., FEBS Lett., 10.1016/S0014-5793(02)02240-8, 512, 1-3, 149-151, 512:149-151, 2002.02.
140. Iida, T., A. Furuta, K. Nishioka, Y. Nakabeppu, and T. Iwaki., Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain., Acta Neuropathol., 103, 1, 20-25, 103:20-25, 2002.01.
141. Matsukura, S., K. Miyazaki, H. Yakushiji, A. Ogawa, K. Harimaya, Y. Nakabeppu, and M. Sekiguchi., Expression and prognostic significance of O6-methylguanine-DNA methyltransferase in hepatocellular, gastric, and breast cancers., Ann. Surg. Oncol., 10.1245/aso.2001.8.10.807, 8, 10, 807-816, 8:807-816, 2001.12.
142. Tsuzuki, T., A. Egashira, H. Igarashi, T. Iwakuma, Y. Nakatsuru, Y. Tominaga, H. Kawate, K. Nakao, K. Nakamura, F. Ide, S. Kura, Y. Nakabeppu, M. Katsuki, T. Ishikawa, and M. Sekiguchi., Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase., Proc. Natl. Acad. Sci. U. S. A., 10.1073/pnas.191086798, 98, 20, 11456-11461, 98:11456-11461, 2001.09.
143. Furuta, A., T. Iida, Y. Nakabeppu, and T. Iwaki., Expression of hMTH1 in the hippocampi of control and Alzheimer's disease., Neuroreport, 10.1097/00001756-200109170-00028, 12, 13, 2895-2899, 12:2895-2899, 2001.09.
144. Jaiswal, M., N. F. LaRusso, K. Nishioka, Y. Nakabeppu, and G. J. Gores., Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide., Cancer Res., 61, 17, 6388-6393, 61:6388-6393, 2001.09.
145. Kasprzak, K. S., Y. Nakabeppu, T. Kakuma, Y. Sakai, K. Tsuruya, M. Sekiguchi, J. M. Ward, B. A. Diwan, K. Nagashima, and B. H. Kasprzak., Intracellular Distribution of the Antimutagenic Enzyme MTH1 in the Liver, Kidney, and Testis of F344 Rats and its Modulation by Cadmium., Exp. Toxico. Pathol., 10.1078/0940-2993-00201, 53, 5, 325-335, 53:325-336, 2001.07.
146. Tsuchimoto, D., Y. Sakai, K. Sakumi, K. Nishioka, M. Sasaki, T. Fujiwara, and Y. Nakabeppu., Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen., Nucleic Acids Res., 10.1093/nar/29.11.2349, 29, 11, 2349-2360, 29:2349-2360., 2001.06.
147. Iida, T., A. Furuta, M. Kawashima, J. Nishida, Y. Nakabeppu, and T. Iwaki., Accumulation of 8-oxo-2'-deoxyguanosine and increased expression of hMTH1 protein in brain tumors., Neuro-oncol., 10.1215/15228517-3-2-73, 3, 2, 73-81, 3:73-81, 2001.04.
148. Rodriguez, J. J., D. R. Garcia, Y. Nakabeppu, and V. M. Pickel., Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration., Exp. Neurol., 10.1006/exnr.2000.7612, 168, 2, 392-401, 168:392-401, 2001.04.
149. Rodriguez, J. J., D. R. Garcia, Y. Nakabeppu, and V. M. Pickel., FosB in rat striatum: normal regional distribution and enhanced expression after 6-month haloperidol administration., Synapse, 10.1002/1098-2396(200102)39:2<122::AID-SYN3>3.0.CO;2-R, 39, 2, 122-132, 39:122-132, 2001.02.
150. Fujikawa, K., H. Kamiya, H. Yakushiji, Y. Nakabeppu, and H. Kasai., Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP., Nucleic Acids Res., 10.1093/nar/29.2.449, 29, 2, 449-454, 29:449-454., 2001.01.
151. Liang, R., H. Igarashi, T. Tsuzuki, Y. Nakabeppu, M. Sekiguchi, K. S. Kasprzak, and Y. H. Shiao., Presence of potential nickel-responsive element(s) in the mouse MTH1 promoter., Ann. Clin. Lab. Sci., 31, 1, 91-98, 31:91-98, 2001.01.
152. Ito, M., M. Akechi, R. Hirose, M. Ichimura, N. Takamatsu, P. Xu, Y. Nakabeppu, S. Tadayoshi, K. Yamamoto, and K. Yoshioka., Isoforms of JSAP1 scaffold protein generated through alternative splicing., Gene, 10.1016/S0378-1119(00)00335-8, 255, 2, 229-234, 255:229-234, 2000.09.
153. Shimokawa, H., Y. Fujii, M. Furuichi, M. Sekiguchi, and Y. Nakabeppu., Functional significance of conserved residues in the phosphohydrolase module of Escherichia coli MutT protein., Nucleic Acids Res., 10.1093/nar/28.17.3240, 28, 17, 3240-3249, 28:3240-3249, 2000.09.
154. Takama, F., T. Kanuma, D. Wang, J. I. Nishida, Y. Nakabeppu, N. Wake, and H. Mizunuma., Mutation analysis of the hMTH1 gene in sporadic human ovarian cancer., Int. J. Oncol., 17, 3, 467-471, 17:467-471, 2000.09.
155. Schwartz, W. J., A. Carpino, Jr., H. O. de la Iglesia, R. Baler, D. C. Klein, Y. Nakabeppu, and N. Aronin., Differential regulation of fos family genes in the ventrolateral and dorsomedial subdivisions of the rat suprachiasmatic nucleus., Neuroscience, 10.1016/S0306-4522(00)00140-8, 98, 3, 535-547, 98:535-547, 2000.06.
156. Miyako, K., C. Takamatsu, S. Umeda, T. Tajiri, M. Furuichi, Y. Nakabeppu, M. Sekiguchi, N. Hamasaki, K. Takeshige, and D. Kang., Accumulation of adenine DNA glycosylase-sensitive sites in human mitochondrial DNA., J. Biol. Chem., 10.1074/jbc.275.16.12326, 275, 16, 12326-12330, 275:12326-12330, 2000.04.
157. Morifuji, M., S. Taniguchi, H. Sakai, Y. Nakabeppu, and M. Ohishi., Differential expression of cytokeratin after orthotopic implantation of newly established human tongue cancer cell lines of defined metastatic ability., Am. J. Pathol., 10.1016/S0002-9440(10)65002-X, 156, 4, 1317-1326, 156:1317-1326, 2000.04.
158. Ohtsubo, T., K. Nishioka, Y. Imaiso, S. Iwai, H. Shimokawa, H. Oda, T. Fujiwara, and Y. Nakabeppu., Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria., Nucleic Acids Res., 10.1093/nar/28.6.1355, 28, 6, 1355-1364, 28:1355-1364, 2000.03.
159. Inoue, R., M. Abe, Y. Nakabeppu, M. Sekiguchi, T. Mori, and T. Suzuki., Characterization of human polymorphic DNA repair methyltransferase. deficient mice., Pharmacogenetics, 10.1097/00008571-200002000-00008, 10, 1, 59-66, 10:59-66, 2000.02.
160. Kawate, H., R. Itoh, K. Sakumi, Y. Nakabeppu, T. Tsuzuki, F. Ide, T. Ishikawa, T. Noda, H. Nawata, and M. Sekiguchi., A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice., Carcinogenesis, 10.1093/carcin/21.2.301, 21, 2, 301-305, 21:301-305, 2000.02.
161. Ohyagi, Y., T. Yamada, K. Nishioka, N. J. Clarke, A. J. Tomlinson, S. Naylor, Y. Nakabeppu, J. Kira, and S. G. Younkin., Selective increase in cellular Ab 42 is related to apoptosis but not necrosis., Neuroreport, 10.1097/00001756-200001170-00033, 11, 1, 167-171, 11:167-171., 2000.01.
162. Kalinichev, M., J. S. Rosenblatt, Y. Nakabeppu, and J. I. Morrell., Induction of c-fos-like and fosB-like immunoreactivity reveals forebrain neuronal populations involved differentially in pup-mediated maternal behavior in juvenile and adult rats., J. Comp. Neurol., 10.1002/(SICI)1096-9861(20000103)416:1<45::AID-CNE5>3.0.CO;2-K, 416, 1, 45-78, 416:45-78., 2000.01.
163. Fujii, Y., H. Shimokawa, M. Sekiguchi, and Y. Nakabeppu., Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins., J. Biol. Chem., 10.1074/jbc.274.53.38251, 274, 53, 38251-38259, 274:38251-38259, 1999.12.
164. Shimura-Miura, H., N. Hattori, D. Kang, K. Miyako, Y. Nakabeppu, and Y. Mizuno., Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in Parkinson's disease., Ann. Neurol., 10.1002/1531-8249(199912)46:6<920::AID-ANA17>3.0.CO;2-R, 46, 6, 920-924, 46:920-924, 1999.11.
165. Oda, H., A. Taketomi, R. Maruyama, R. Itoh, K. Nishioka, H. Yakushiji, T. Suzuki, M. Sekiguchi, and Y. Nakabeppu., Multi-forms of human MTH1 polypeptides produced by alternative translation initiation and single nucleotide polymorphism., Nucleic Acids Res., 10.1093/nar/27.22.4335, 27, 22, 4335-4343, 27:4335-4343, 1999.11.
166. Ito, M., K. Yoshioka, M. Akechi, S. Yamashita, N. Takamatsu, K. Sugiyama, M. Hibi, Y. Nakabeppu, T. Shiba, and K. I. Yamamoto., JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway., Mol. Cell. Biol., 19, 11, 7539-7548, 19:7539-7548., 1999.11.
167. Fujikawa, K., H. Kamiya, H. Yakushiji, Y. Fujii, Y. Nakabeppu, and H. Kasai., The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein., J. Biol. Chem., 10.1074/jbc.274.26.18201, 274, 26, 18201-18205, 274:18201-18205., 1999.06.
168. Nishioka, K., T. Ohtsubo, H. Oda, T. Fujiwara, D. Kang, K. Sugimachi, and Y. Nakabeppu., Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs., Mol. Biol. Cell, 10, 5, 1637-1652, 10:1637-1652., 1999.05.
169. Hayakawa, H., A. Hofer, L. Thelander, S. Kitajima, Y. Cai, S. Oshiro, H. Yakushiji, Y. Nakabeppu, M. Kuwano, and M. Sekiguchi., Metabolic fate of oxidized guanine ribonucleotides in mammalian cells., Biochemistry, 10.1021/bi982361l, 38, 12, 3610-3614, 38:3610-3614., 1999.03.
170. Ohtsubo, T., O. Matsuda, K. Iba, I. Terashima, M. Sekiguchi, and Y. Nakabeppu., Molecular cloning of AtMMH, an Arabidopsis thaliana ortholog of the Escherichia coli mutM gene, and analysis of functional domains of its product., Mol. Gen. Genet., 259, 6, 577-590, 259:577-590., 1998.10.
171. McGahan, L., A. M. Hakim, Y. Nakabeppu, and G. S. Robertson., Ischemia-induced CA1 neuronal death is preceded by elevated FosB and Jun expression and reduced NGFI-A and JunB levels., Mol. Brain. Res., 10.1016/S0169-328X(98)00039-4, 56, 1-2, 146-161, 56:146-161., 1998.05.
172. Hazell, A. S., L. McGahan, W. Tetzlaff, A. M. Bedard, G. S. Robertson, Y. Nakabeppu, and A. M. Hakim., Immediate-early gene expression in the brain of the thiamine-deficient rat., J .Mol. Neurosci., 10:1-15, 1998.02.
173. Crocker, S. J., M. Morelli, N. Wigle, Y. Nakabeppu, and G. S. Robertson., D1-Receptor-related priming is attenuated by antisense-meditated 'knockdown' of fosB expression., Mol. Brain. Res., 10.1016/S0169-328X(97)00281-7, 53, 1-2, 69-77, 53:69-77, 1998.01.

九大関連コンテンツ