Details of a Researcher - SUZUKI Hiromu

Papers - SUZUKI Hiromu

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Proteins interacting with CHFR, mitotic-checkpoint ubiquitin ligase

Mita H, Toyota M, Sasaki Y, Suzuki H, Idogawa M, Kashima L, Tokino T

Tumor Research ( Sapporo Medical University ) 41 23 - 41 2006.12 [Refereed]

Cell cycle progression is monitored by checkpoint mechanisms to ensure the integrity of the genome. CHFR which contains a RING domain and has ubiquitin ligase activity, a novel mitotic checkpoint gene, delays chromosome condensation in cells treated with microtubule poisons. CHFR is inactivated by promoter methylation and point mutations in various human tumors, and cancer cells lacking CHFR are sensitive to microtubule inhibitors. However, few reports are available on the molecular mechanism that accounts for the link between the sensitivity of cancer cells to microtubule inhibitors and the physiological function of CHFR. In the present study, we isolated cellular proteins capable of interacting with CHFR using yeast two-hybrid method to clarify the function of CHFR. As a result of the screening, we isolated canonical and noncanonical E2 ubiquitin conjugating enzymes as CHFR interacting proteins, which are involved in proteolytic and non-proteolytic ubiquitination respectively. This raises the possibility that CHFR is switching canonical and non-canonical ubiquitination depending on the situation of cells. On the other hand, we isolated gadd34 which interacted with the FHA domain of CHFR by two-hybrid screen. Coexpression in mammalian cells showed that gadd34 interacted with the FHA domain of CHFR, but gadd34 is not the substrate for CHFR, rather it promoted autoubiquitination of CHFR. Furthermore, CHFR moved, in part, from nucleus to cytoplasm in the presence of microtubule inhibitor docetaxel, which enabled colocalization of CHFR and gadd34 in cytoplasm. This colocalization was followed by cell death. These findings suggest that gadd34 and CHFR cooperate to mediate cell death in response to mitotic stress.

DOI CiNii

インシリコ解析による新規p53標的遺伝子群の網羅的な同定

丸山玲緒, 豊田実, 明石浩史, 佐々木泰史, 青木文夫, 鈴木拓, 見田裕章, 井戸川雅史, 今井浩三, 篠村泰久, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 65回 79 - 79 2006.09

短いDNA断片の塩基配列情報を用いた定量的ゲノム解析法の開発と癌研究への応用

見田裕章, 豊田実, 丸山玲緒, 明石浩史, 青木文夫, 佐々木泰史, 鹿島理沙, 鈴木拓, 井戸川雅史, 苗代康可, 今井浩三, 篠村恭久, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 65回 182 - 182 2006.09

CHFR(checkpoint with FHA and RING domain)によるNF-kBシグナリング制御

鹿島理沙, 見田裕章, 豊田実, 佐々木泰史, 井戸川雅史, 鈴木拓, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 65回 162 - 162 2006.09

口腔扁平上皮癌におけるRAS関連遺伝子のジェネティックおよびエピジェネティックな異常の解析

今井崇, 秋野公臣, 豊田実, 鈴木拓, 佐々木泰史, 見田裕章, 井戸川雅史, 荻和弘, 鹿島理沙, 曽我部陽平, 今井浩三, 平塚博義, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 65回 199 - 199 2006.09

大腸癌におけるエピジェネティックな変化を指標とした診断への比較検討

渡邊嘉行, 豊田実, 鈴木拓, 岡本賢, 時野隆至, 伊東文生

日本癌学会総会記事 ( (一社)日本癌学会 ) 65回 52 - 52 2006.09

Activation of the ribosomal protein L13 gene in human gastrointestinal cancer

T Kobayashi, Y Sasaki, Y Oshima, H Yamamoto, H Mita, H Suzuki, M Toyota, T Tokino, F Itoh, K Imai, Y Shinomura

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE ( PROFESSOR D A SPANDIDOS ) 18 ( 1 ) 161 - 170 2006.07 [Refereed]

Although ribosomal proteins are major components of ribosomes, recent data have shown them to have extraribosomal functions apart from ribosome and protein biosynthesis. In our earlier study, we showed that ribosomal protein L13 mRNA was up-regulated in response to DNA damage in hamster cells. We report here that L13 expression is up-regulated in human gastrointestinal cancers. We also examined the biological role of L13 on human cancer cells. Knocking down L13 expression using small interfering RNA (siRNA) resulted in drastic attenuation of cancer cell growth with significant G1 and G2/M arrest of the cell cycle. Moreover, L13 siRNA significantly enhanced the cellular sensitivity to certain DNA damaging agents and, concordantly, L13-overexpressing cells demonstrated greater chemoresistance compared to parent cells, suggesting an inverse correlation between L13 expression and chemosensitivity. By using semi-quantitative RT-PCR, we analyzed expression of L13 in freshly resected cancer tissue of the stomach, colorectum and liver. Up-regulation of L 13 mRNA expression was observed in 10 (28%) of 36 gastric, 19 (41%) of 46 colorectal and 5 (20%) of 25 liver cancer tissue samples compared to adjacent normal tissue samples. We also found that increased expression of the L13 gene correlated with clinical staging in gastric cancers. The results of this study suggest that L13 plays an essential role in the progression of some gastrointestinal malignancies.

PubMed

DNA断片の塩基配列情報に基づいたゲノムコピー数解析法の開発

見田裕章, 豊田実, 丸山玲緒, 青木文夫, 明石浩史, 鹿島理沙, 佐々木泰史, 鈴木拓, 井戸川雅史, 藤井恭子, 篠村恭久, 今井浩三, 時野隆至

日本臨床分子医学会学術総会プログラム・抄録集 ( 日本臨床分子医学会 ) 43回 63 - 63 2006.07

がん抑制遺伝子p53により誘導される新規分子の網羅的同定

丸山玲緒, 豊田実, 青木文夫, 佐々木泰史, 明石浩史, 鈴木拓, 見田裕章, 時野隆至, 今井浩三, 篠村恭久

日本臨床分子医学会学術総会プログラム・抄録集 ( 日本臨床分子医学会 ) 43回 64 - 64 2006.07

Mammary gland tissue targeted overexpression of human protease-activated receptor 1 reveals a novel link to beta-catenin stabilization

YJ Yin, Katz, V, Z Salah, M Maoz, Cohen, I, B Uziely, H Turm, S Grisaru-Granovsky, H Suzuki, R Bar-Shavit

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 66 ( 10 ) 5224 - 5233 2006.05 [Refereed]

Protease-activated receptor 1 (PAR1) is emerging with distinct assignments in tumor biology. We show that tissue targeted overexpression of hPar1 in mice mammary glands results in precocious hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. These glands exhibit increased levels of wnt-4 and wnt-7b and a striking beta-catenin stabilization. Nuclear localization of beta-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PARI induces beta-catenin nuclear localization also in established epithelial tumor cell lines of intact beta-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PARI-mediated beta-catenin stabilization is taking place primarily via the increase of Wnt expression. Enforced expression of a specific Wnt antagonist family member, secreted frizzled receptor protein 5 (SFRP5), efficiently inhibited PAR1-induced beta-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced beta-catenin nuclear accumulation. This takes place most likely via inhibition of Wnt signaling at the level of cell surface (forming a neutralizing complex of "Receptors-SFRP-Wnt"). Furthermore, depletion of hPar1 by small interfering RNA (siRNA) vectors markedly inhibited PARI-induced Wnt-4. The striking stabilization of beta-catenin, inhibited by SFRPs on one hand and Wnt-4 silencing by hPar-1 siRNA on the other hand, points to a novel role of hPar1 in Wnt-mediated beta-catenin stabilization. This link between PAR1 and beta-catenin may bear substantial implications both in developmental and tumor progression processes.

DOI PubMed

Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation

R Maruyama, F Aoki, M Toyota, Y Sasaki, H Akashi, H Mita, H Suzuki, K Akino, M Ohe-Toyota, Y Maruyama, H Tatsumi, K Imai, Y Shinomura, T Tokino

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 66 ( 9 ) 4574 - 4583 2006.05 [Refereed]

p53 is the most frequently mutated tumor suppressor gene in human neoplasia and encodes a transcriptional coactivator. Identification of p53 target genes is therefore key to understanding the role of p53 in tumorigenesis. To identify novel p53 target genes, we first used a comparative genomics approach to identify p53 binding sequences conserved in the human and mouse genome. We hypothesized that potential p53 binding sequences that are conserved are more likely to be functional. Using stringent filtering procedures, 32 genes were newly identified as putative p53 targets, and their responsiveness to p53 in human cancer cells was confirmed by reverse transcription-PCR and real-time PCR. Among them, we focused on the vitamin D receptor (VDR) gene because vitamin D3 has recently been used for chemoprevention of human tumors. VDR is induced by p53 as well as several other p53 family members, and analysis of chromatin immunoprecipitation showed that p53 protein binds to conserved intronic sequences of the VDR gene in vivo. Introduction of VDR into cells resulted in induction of several genes known to be p53 targets and suppression of colorectal cancer cell growth. In addition, p53 induced VDR target genes in a vitamin D3-dependent manner. Our in silico, approach is a powerful method for identification of functional p53 binding sites and p53 target genes that are conserved among humans and other organisms and for further understanding the function of p53 in tumorigenesis.

DOI PubMed

Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus

M Kusano, M Toyota, H Suzuki, K Akino, F Aoki, M Fujita, M Hosokawa, Y Shinomura, K Imai, T Tokino

CANCER ( JOHN WILEY & SONS INC ) 106 ( 7 ) 1467 - 1479 2006.04 [Refereed]

BACKGROUND. The CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis. METHODS. Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined-restriction analysis. Epstein-Barr virus (EBV)-associated gastric tumors bisulfite were detected using real-time polymerase chain reaction analysis followed by all evaluation of the correlations between CIMP status, EBV-association, and genetic alteration of p53 and K-ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP-H) with tumors that had low CIMP methylation (CIMP-L) or negative CIMP methylation (CIMP-N). RESULTS. The methylation profiles of 12 genes showed non-random methylation, Supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP-H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K-ras. In a multiple logistic regression model with CIMP-H as the dependent variable, proximal location (P =.011), diffuse type (P =.019), and less advanced pathologic TNM status (P =.043) contributed significantly to CIMP-H. Patients who had CIMP-N gastric tumors had a significantly worse Survival than patients who had CIMP-H tumors (P =.004) or CIMP-L tumors (P =.012). EBV-associated tumors were associated strongly with CIMP-H, hypermethylation of tumor-related genes, and no p53 or K-ras mutation. CONCLUSIONS. CIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis.

DOI PubMed

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.

Terasawa K, Toyota M, Sagae S, Ogi K, Suzuki H, Sonoda T, Akino K, Maruyama R, Nishikawa N, Imai K, Shinomura Y, Saito T, Tokino T

British journal of cancer ( 6 ) 94 914 - 921 2006.03 [Refereed]

DOI PubMed

Smoking, drinking, sleeping habits, and other lifestyle factors and the risk of systemic lupus erythematosus in Japanese females: Findings from the KYSS study

Masakazu Washio, Takahiko Horiuchi, Chikako Kiyohara, Hiroko Kodama, Yoshifumi Tada, Toyoko Asami, Hiroki Takahashi, Gen Kobashi, Takashi Abe, Hisato Tanaka, Norihiko Nogami, Mine Harada, Hiroshi Tsukamoto, Saburo Ide, Kohei Nagasawa, Osamu Ushiyama, Takao Hotokebuchi, Kazushi Okamoto, Naomasa Sakamoto, Satoshi Sasaki, Yoshihiro Miyake, Tetsuji Yokoyama, Mitsuru Mori, Asae Oura, Yasuhisa Sinomura, Hiromu Suzuki, Motohisa Yamamoto, Yutaka Inaba, Masaki Nagai

Modern Rheumatology 16 ( 3 ) 143 - 150 2006.03 [Refereed]

Many risk factors have been proposed for systemic lupus erythematosus (SLE). However, there is little information about the relationship between lifestyles and SLE in Japan. Two case control studies were conducted in Kyushu, southern Japan, and in Hokkaido, northern Japan, to examine the relationship between lifestyles and development of SLE in females. The participants were 78 patients and 329 controls in Kyushu and 35 patients and 188 controls in Hokkaido. Smoking was associated with an increased risk of SLE after adjusting for age in both regions. However, in Hokkaido, this association between smoking and SLE did not reach statistical significance after adjusting for alcohol drinking. The present study suggests that smoking may increase the risk of SLE among Japanese females. © Japan College of Rheumatology 2006.

DOI PubMed

De novo CpG island methylation in human cancer cells

KW Jair, KE Bachman, H Suzuki, AH Ting, Rhee, I, RWC Yen, SB Baylin, KE Schuebel

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 66 ( 2 ) 682 - 692 2006.01 [Refereed]

A major obstacle toward understanding how patterns of abnormal mammalian cytosine DNA methylation are established is the difficulty in quantitating the de novo methylation activities of DNA methyltransferases (DNMT) thought to catalyze these reactions. Here, we describe a novel method, using native human CpG island substrates from genes that frequently become hypermethylated in cancer, which generates robust activity for measuring de novo CpG methylation. We then survey colon cancer cells with genetically engineered deficiencies in different DNMTs and find that the major activity against these substrates in extracts of these cells is DNMT1, with minor contribution from DNMT3b and none from DNMT3a, the only known bona fide de novo methyltransferases. The activity of DNMT1 against unmethylated CpG rich DNA was further tested by introducing CpG island substrates and DNMT1 into Drosophila melanogaster cells. The exogenous DNMT1 methylates the integrated mammalian CpG islands but not the Drosophila DNA. Additionally, in human cancer cells lacking DNMT1 and DNMT3b and having nearly absent genomic methylation, gene-specific de novo methylation can be initiated by reintroduction of DNMT1. Our studies provide a new assay for de novo activity of DNMTs and data suggesting a potential role for DNMT1 in the initiation of promoter CpG island hypermethylation in human cancer cells.

DOI PubMed

Roles and causes of abnormal DNA methylation in gastrointestinal cancers

Hiromu Suzuki, Minoru Toyota, Hironobu Sato, Tomoko Sonoda, Fumio Sakauchi, Mitsuru Mori

Asian Pacific Journal of Cancer Prevention ( Asian Pacific Organization for Cancer Prevention ) 7 ( 2 ) 177 - 185 2006 [Refereed]

Evidence now suggests that epigenetic abnormalities, particularly altered DNA methylation, play a crucial role in the development and progression of human gastrointestinal malignancies. Two distinct DNA methylation abnormalities are observed together in cancer. One is an overall genome-wide reduction in DNA methylation (global hypomethylation) and the other is regional hypermethylation within the CpG islands of specific gene promoters. Global hypomethylation is believed to induce proto-oncogene activation and chromosomal instability, whereas regional hypermethylation is strongly associated with transcriptional silencing of tumor suppressor genes. To date, genes involved in regulation of the cell cycle, DNA repair, growth signaling, angiogenesis, and apoptosis, are all known to be inactivated by hypermethylation. Recently developed techniques for detecting changes in DNA methylation have dramatically enhanced our understanding of the patterns of methylation that occur as cancers progress. One of the key contributors to aberrant methylation is aging, but other patterns of methylation are cancer-specific and detected only in a subset of tumors exhibiting the CpG island methylator phenotype (CIMP). Although the cause of altered patterns of DNA methylation in cancer remsains unknown, it is believed that epidemiological factors, notably dietary folate intake, might strongly influence DNA methylation patterns. Recent studies further suggest that polymorphisms of genes involved in folate metabolism are causally related to the development of cancer. Identifying epidemiological factors responsible for epigenetic changes should provide clues for cancer prevention in the future.

PubMed

Application of methylation changes in a novel colon tumor suppressor gene, RASSF2, to tumor marker

Toyota Minoru, Akino Kimishige, Suzuki Hiromu, Tokino akashi, Shinomura Y, Imai Kohzoh

Japan Journal of Molecular Tumor Marker Research ( Japanese Society for Molecular Tumor Marker Research ) 21 5 - 6 2006

DOI CiNii

分裂期チェックポイント分子CHFRの結合分子探索と機能解析

見田裕章, 豊田実, 鹿島理沙, 佐々木泰史, 秋野公臣, 鈴木拓, 井戸川雅史, 下重美紀, 山田哲司, 篠村恭久, 今井浩三, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 64回 327 - 327 2005.09

RASエフェクター,RASSF2遺伝子は大腸がんにおける新規がん抑制遺伝子である(The Ras Effector RASSF2 is a Novel Tumor Suppressor Gene in Human Colorectal Cancer)

秋野公臣, 豊田実, 鈴木拓, 見田裕章, 佐々木泰史, 篠村恭久, 今井浩三, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 64回 136 - 137 2005.09

DNAの異常メチル化を指標とした大腸癌アベレージリスク群の設定と検診への応用

渡邊嘉行, 豊田実, 秋野公臣, 鈴木拓, 前畑忠照, 岡本賢, 奥瀬千晃, 今井浩三, 篠村恭久, 伊東文生, 時野隆至

日本癌学会総会記事 ( (一社)日本癌学会 ) 64回 540 - 540 2005.09

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Papers - SUZUKI Hiromu