Details of a Researcher - TOKINO Takashi

Misc - TOKINO Takashi

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消化器癌におけるTCF2遺伝子のエピジェネティックな異常

丸山玲緒, 豊田実, 荻和弘, 鈴木拓, 秋野公臣, 佐々木泰史, 見田裕章, 佐藤亜由美, 時野隆至

日本癌学会総会記事 62nd 2003

J-GLOBAL

p53ファミリーの抗腫よう活性と癌治療への応用

佐々木泰史, 苗代康可, 今井浩三, 山下利春, 時野隆至

日本癌治療学会誌 38 ( 2 ) 2003

J-GLOBAL

全ゲノム配列を対象とするsequence motif解析システムの開発と臨床応用

明石浩史, 豊田実, 青木文夫, 佐々木泰史, 見田裕章, 辰巳治之, 時野隆至, 今井浩三

日本癌学会総会記事 62nd 2003

J-GLOBAL

M期チェックポイント遺伝子CHFRの機能解析

見田裕章, 豊田実, 佐藤亜由美, 荻和弘, 佐々木泰史, 苗代康可, 秋野公臣, 今井浩三, 時野隆至

日本分子生物学会年会プログラム・講演要旨集 26th 2003

J-GLOBAL

p53ファミリーのアポトーシス誘導活性と癌治療への応用

佐々木泰史, 時野隆至, 今井浩三

日本内科学会雑誌 92 2003

J-GLOBAL

【p53経路とRB経路ここまでわかった細胞癌化のメカニズム】 p53ファミリーの新しい機能

佐々木泰史, 時野隆至

細胞工学 ( (株)学研メディカル秀潤社 ) 22 ( 1 ) 34 - 38 2002.12

p53ファミリー遺伝子はp53と高い相同性を有するが,ヒト癌における遺伝子変異の頻度は低く,p53ファミリーメンバーの生体での役割はp53自身とは異なることが予想される.cDNAマイクロアレイ解析によって,Notch受容体のリガンドをコードするJAG1及びJAG2遺伝子がp63及びp73によって特異的に発現上昇することを見つけた.p63遺伝子の機能の少なくとも一部はJAG1/2を介して細胞,組織の分化・発生に深く関与していることが明らかになってきた.p53依存性アポトーシスにおけるp53ファミリーメンバーの役割について言及した

The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors.

Hiroyuki Nishimori, Yasushi Sasaki, Koichi Yoshida, Hideto Irifune, Hitoshi Zembutsu, Toshihiro Tanaka, Tomoki Aoyama, Taisuke Hosaka, Satoshi Kawaguchi, Takuro Wada, Jun-Ichi Hata, Junya Toguchida, Yusuke Nakamura, Takashi Tokino

Oncogene 21 ( 54 ) 8302 - 9 2002.11 [Refereed] [International journal]

We report here that the Id2 (inhibitor of DNA binding 2) gene is a novel target of transcriptional activation by EWS-FLI1 and EWS-ERG, two fusion proteins that characterize Ewing family tumors (EFTs). To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line by retroviral transduction. cDNA microarray analysis revealed that Id2 expression was up-regulated by introducing the EWS-ETS fusion gene but not by the normal full-length ETS gene. An Id2 promoter-luciferase reporter assay showed that transactivation by EWS-ETS involves the minimal Id2 promoter and may function in cooperation with c-Myc within the full-length regulatory region. A chromatin immunoprecipitation assay revealed direct interaction between the Id2 promoter and EWS-FLI1 fusion protein in vivo. Significantly higher expression of Id2 and c-Myc was observed in all of the six EFT cell lines examined compared to six other sarcoma cell lines. Moreover, high levels of Id2 expression were also observed in five of the six primary tumors examined. Id2 is generally thought to affect the balance between cell differentiation and proliferation in development and is highly expressed in several cancer types. Considering these previous studies, our data suggest that the oncogenic effect of EWS-ETS may be mediated in part by up-regulating Id2 expression. doi:10.1038/sj.onc.1206025

DOI PubMed

高速並列処理技術を用いたウェブベース全ゲノム解析システムの開発とその評価

明石浩史, 青木文夫, 豊田実, 佐々木泰史, 中村正弘, 大西浩文, 戸倉一, 西城一翼, 伊東文生, 今井浩三, 時野隆至, 辰巳治之

医療情報学連合大会論文集 ( (一社)日本医療情報学会 ) 22回 252 - 253 2002.11

DNA methylation changes in gastrointestinal disease.

Minoru Toyota, Fumio Itoh, Takefumi Kikuchi, Ayumi Satoh, Toshiro Obata, Hiromu Suzuki, Suguru Ishii, Takao Endo, Takashi Tokino, Kohzoh Imai

Journal of gastroenterology 37 Suppl 14 97 - 101 2002.11 [Refereed] [Domestic journal]

DNA methylation of the 5' region of genes is often associated with gene silencing in X-chromosome inactivation and imprinting. Recent studies have indicated that altered DNA methylation plays a role in the inactivation of multiple tumor suppressor genes and DNA repair genes such as p16INK4A and hMLH1. Colorectal adenomas have a relatively high frequency of methylation, and aberrant methylation is an early event during tumorigenesis. In aging patients, even colon epithelium which appears to be normal showed a significant amount of methylation in a subset of the genes. Colon mucosa from patients with inflammatory bowel disease also showed a high level of methylation. DNA methylation can be a specific diagnostic marker in gastrointestinal cancer and inflammatory bowel disease, for which there is no perfect marker for a noninvasive diagnosis.

PubMed

Aberrant methylation of multiple genes and clinicopathological features in oral squamous cell carcinoma.

Kazuhiro Ogi, Minoru Toyota, Mutsumi Ohe-Toyota, Nobuyuki Tanaka, Makoto Noguchi, Tomoko Sonoda, Geniku Kohama, Takashi Tokino

Clinical cancer research : an official journal of the American Association for Cancer Research 8 ( 10 ) 3164 - 71 2002.10 [Refereed] [International journal]

The purpose of this study was to examine the methylation profile of various oral squamous cell carcinomas and to correlate the methylation of particular chromosomal loci with the clinicopathological features of the tumors. A semiquantitative analysis of the methylation status of 12 loci in 96 primary tumors and 13 cell lines was carried out. Methylation frequency was calculated as the percentage of methylated alleles detected by bisulfate-PCR. Of the 12 loci examined, 9 (p16INK4A, p15INK4B, p14ARF, DCC, DAP kinase, MINT1, MINT2, MINT27, and MINT31) exhibited aberrant methylation at various frequencies, whereas 3 (hMLH1, HRK, and CACNA1G) showed no methylation. Dense methylation of the 5' CpG island of DAP kinase and MINT1 was well correlated with loss of gene expression. In addition, methylation of DCC was correlated with bone invasion by gingival tumors (P = 0.036), with aggressive invasiveness of tumors of the tongue (P = 0.046), and with reduced survival (P = 0.050). Methylation of MINT1 and MINT31 also correlated with poor prognoses (P = 0.058 and 0.041), whereas methylation of p14ARF correlated with a good prognosis (P = 0.021). Cox regression analysis showed methylation of MINT31 to be an independent predictor of outcome (hazard ratio, 3.79; 95% confidence interval, 1.58-9.10) and to be associated with the T4 disease group (hazard ratio, 5.71; 95% confidence interval, 1.25-26.07). Analysis of DNA methylation is a useful approach to evaluation of the biological characteristics of oral cancers and may be a useful diagnostic indicator of patient prognosis.

PubMed

DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers

A Satoh, M Toyota, F Itoh, T Kikuchi, T Obata, Y Sasaki, H Suzuki, A Yawata, M Kusano, M Fujita, M Hosokawa, K Yanagihara, T Tokino, K Imai

BRITISH JOURNAL OF CANCER ( NATURE PUBLISHING GROUP ) 86 ( 11 ) 1817 - 1823 2002.06

Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon, To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5' CpG island of the death-associated protein kinase gene. Methylation of the 5' CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5' CpG island, and treatment with 5-aza-2'-deoxycitidine, a methyltransferase inhibitor, restored gene expression, Acetylation of histones H3 and H4 in the 5' region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation, Thus, aberrant DNA methylation and histone deacetylation of the 5' CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies.

DOI

Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors.

Takefumi Kikuchi, Minoru Toyota, Fumio Itoh, Hiromu Suzuki, Toshiro Obata, Hiroyuki Yamamoto, Hideki Kakiuchi, Masanobu Kusano, Jean-Pierre J Issa, Takashi Tokino, Kohzoh Imai

Oncogene 21 ( 17 ) 2741 - 9 2002.04 [Refereed] [International journal]

To clarify the role of DNA methylation in the silencing of the expression of cyclin-dependent kinase inhibitor p57KIP2 seen in certain tumors, we investigated the methylation status of its 5' CpG island in various tumor cell lines and primary cancers. Dense methylation of the region around the transcription start site was detected in 1 out of 10 colorectal, 2 out of 8 gastric, and 6 out of 14 hematopoietic tumor cell lines and in 5 out of 35 (14%) gastric, 6 out of 20 (30%) hepatocellular, and 2 out of 18 (11%) pancreatic cancers; 7 out of 25 (28%) acute myeloid leukemia cases also showed methylation of the p57KIP2 gene, which strongly correlated with the CpG island methylator phenotype (P<0.001). Detailed mapping revealed that dense methylation of the region around the transcription start site (-300 to +400), but not of the edges of the CpG island, was closely associated with gene silencing. 5-aza-2'-deoxycytidine, a methyltransferase inhibitor, restored expression of p57KIP2, and chromatin immunoprecipitation using anti-histone H3 and H4 antibodies showed histone to be deacetylated in cell lines where p57KIP2 was methylated at the transcription start site. Regional methylation and histone deacetylation thus appear to be crucially involved in the silencing of p57KIP2 expression in human tumors.

DOI PubMed

Detection of human papillomavirus DNA by PCR/microfluorometry for screening of cervical cancer.

Akihiro Yamaguchi, Naoko Hashimoto, Wataru Tsutae, Kuniyoshi Seino, Yasuhiko Ebina, Takashi Tokino, Noriyuki Sato, Kokichi Kikuchi

Clinica chimica acta; international journal of clinical chemistry 318 ( 1-2 ) 41 - 9 2002.04 [Refereed] [International journal]

BACKGROUND: Cervical cancer screening is conducted by a cytological Papanicolaou (Pap) test. For screening, it is becoming increasingly important to introduce a more objective result, based on human papillomavirus (HPV) DNA test. We describe here a practical method allowing the mass detection of HPV-DNA by PCR followed by fluorogenic DNA intercalation. METHODS: Samples used were cervical scrapes or biopsy specimens obtained from women who had undergone cytological testing for cervical cancer. Crude DNAs were extracted by a simplified proteinase K-boil method. Common and type-specific primers were newly designed for major types of high-risk HPVs. A fluorogenic DNA intercalator, SYBR Green I was directly added to the specific PCR products. The resultant fluorescence was measured by a conventional fluorometric microplate reader. RESULTS: The proposed PCR/microfluorometry (MFL) allowed a simple, rapid and economical detection of HPV-DNA without any use of labeling primers or probes. HPV-DNAs were found in 48.2% (123/255) of the cervical scrapes. The detection rate of HPV in cervical cancer biopsy specimen was 92.4% (61/66). CONCLUSIONS: PCR/MFL detection of HPV-DNA, followed by combined type-specific PCR, is expected to be an extremely useful tool in cervical cancer screening.

DOI PubMed

p53ファミリー遺伝子,p63とp73の個性

佐々木泰史, 時野隆至

最新医学 ( (株)最新医学社 ) 57 ( 4 ) 947 - 951 2002.04

Identification of the osteopontin gene as a direct target of TP53.

Ichiro Morimoto, Yasushi Sasaki, Setsuko Ishida, Kohzoh Imai, Takashi Tokino

Genes, chromosomes & cancer 33 ( 3 ) 270 - 8 2002.03 [Refereed] [International journal]

The TP53 tumor suppressor gene regulates a number of genes that are involved in cell-cycle inhibition, apoptosis, and maintaining genetic stability. Recently, two genes that have a role in immunosurveillance were identified as downstream targets of TP53. These genes, TAP1 and fractalkine, may contribute to suppress tumor growth through host immunosurveillance. It has been reported that the mouse secreted phosphoprotein osteopontin (Opn) is one of the key cytokines for type 1 immune responses mediated by macrophages. It also was reported that Opn may play a role in suppressing tumor growth in vivo. Here we identified Opn as a Tp53-target gene using mRNA differential display analysis of embryonic fibroblasts from Tp53-deficient mice. Furthermore, we found that Opn expression was upregulated by DNA damage-induced Tp53 activity and by adenovirus-mediated transfer of the human TP53 gene. In addition, a luciferase assay showed that the Opn gene has a functional Tp53-responsive element in its promoter region, and a chromatin immunoprecipitation assay confirmed interaction between the Opn promoter and Tp53 protein in vivo. These results suggest that OPN is a direct transcriptional target of TP53. The TP53-directed regulation of OPN expression suggests a novel model of TP53 participation in immunosurveillance, involving interaction with the host immune system to prevent damaged cells from undergoing malignant transformation.

DOI PubMed

The p53 family member genes are involved in the Notch signal pathway.

Yasushi Sasaki, Setsuko Ishida, Ichiro Morimoto, Toshiharu Yamashita, Takashi Kojima, Chikashi Kihara, Toshihiro Tanaka, Kohzoh Imai, Yusuke Nakamura, Takashi Tokino

The Journal of biological chemistry 277 ( 1 ) 719 - 24 2002.01 [Refereed] [International journal]

The p53 tumor suppressor is a transcription factor that regulates cell growth and death in response to environmental stimuli such as DNA damage. p63/p51 and p73 were recently identified as members of the p53 gene family. In contrast to p53 however, p63 and p73 are rarely mutated in human cancers. Mice that lack p53 are developmentally normal, while p63 and p73 appear to play critical roles in normal development. To determine how p63 and p73 are involved in normal development, we attempted to identify target genes that are specifically regulated by p63 and/or p73 but not by p53. We found that the Jagged1 (JAG1) and Jagged2 (JAG2) genes, encoding ligands for the Notch receptors, are up-regulated by p63 and p73. Furthermore, we identified a p63-binding site in the second intron of the JAG1 gene, which can directly interact with the p63 protein in vivo, as assessed by a chromatin immunoprecipitation assay. A heterologous reporter assay revealed that this p63-binding site is a functional response element and is specific for p63. We also found a target of Notch signaling, HES-1 was up-regulated in Jurkat cells, in which Notch1 is highly expressed, when co-cultured with p63-transfected cells, suggesting that p63 can trigger the Notch signal pathway in neighboring cells. Our findings show an association between the p53 family genes and Notch signaling and suggest a potential molecular mechanism for the involvement of the p53 family genes in normal development.

DOI PubMed CiNii

新しいp53標的遺伝子SCBP1の同定と機能解析

足立賢哉, 豊田実, 佐々木泰史, 石田勢津子, 斉藤豪, 工藤隆一, 時野隆至

日本癌学会総会記事 61st 2002

J-GLOBAL

DNAメチル化による遺伝子不活化の分子機構

豊田実, 菊地剛史, 佐藤亜由美, 佐々木泰史, 小畑俊郎, 秋野公臣, 鈴木拓, 時野隆至, 今井浩三

日本癌学会総会記事 61st 2002

J-GLOBAL

消化器癌におけるアポトーシス関連遺伝子Hrkの異常メチル化

小畑俊郎, 豊田実, 佐々木泰史, 佐藤亜由美, 菊地剛史, 鈴木拓, 伊東文生, 時野隆至, 今井浩三

日本癌学会総会記事 61st 2002