研究者詳細 - 井戸川　雅史

論文 - 井戸川　雅史

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CHFR有糸分裂チェックポイントタンパク質はNFκBの転写活性を抑制する(CHFR mitotic checkpoint protein inhibits the transcriptional activity of NF-κB)

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

日本癌学会総会記事 ( (一社)日本癌学会 ) 66回 482 - 482 2007年08月

口腔癌におけるRAS関連遺伝子の異常について(Alterations of RAS signaling pathway in oral squamous cell carcinoma)

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, 鹿島理沙, 曽我部陽平, 渡邊嘉行, 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 ) 66回 314 - 314 2007年08月

デジタルゲノムスキャンにより同定された胃癌におけるK-rasゲノム増幅(Genomic amplification of K-ras in gastric cancer identified by digital genome scanning)

見田裕章, 豊田実, 青木文夫, 明石浩史, 丸山玲緒, 佐々木泰史, 鈴木拓, 井戸川雅史, 鹿島理沙, 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 ) 66回 231 - 231 2007年08月

Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines

Yuichiro Oshima, Yasushi Sasaki, Hideaki Negishi, Masashi Idogawa, Minoru Toyota, Toshiharu Yamashita, Takuro Wada, Satoshi Nagoya, Satoshi Kawaguchi, Toshihiko Yamashita, Takashi Tokino

CANCER BIOLOGY & THERAPY ( LANDES BIOSCIENCE ) 6 ( 7 ) 1058 - 1066 2007年07月 [査読有り]

Osteosarcoma (OS) is one of the most common malignancies of the bone. Although prognosis of OS has improved significantly during the past several years due to more intensive chemotherapy and radiotherapy regimens, new therapeutic approaches are needed for recurrent and inoperable cases. p73 and p63, like their homologue, the tumor suppressor p53, are able to induce apoptosis in several cell types. Here, we evaluated the antitumor effects of p73 and p63 on eleven different human OS cell lines. In vitro, adenovirus-mediated transduction of p63 gamma induced apoptosis in OS cells that are resistant to p53-mediated apoptosis, while less effect was observed following transduction of p73 alpha or p63 alpha. Interestingly, the apoptotic effects of p63 gamma were greater than those of wild-type p53 in OS cells carrying MDM2-amplification. We then determined the in vivo therapeutic effect of intratumoral injection of adenovirus-vector expressing p53 family members on xenografts derived from Saos-2 cells implanted in nude mice, and showed that infection with p63 gamma significantly suppressed tumor growth compared with p53. In addition, exogenous p73 beta and p63 gamma significantly increased the chemosensitivity of OS cells to doxorubicin and cisplatin, chemotherapeutic agents commonly used in the treatment of OS. Our results suggest that adenovirus-mediated transduction of p53 family members may have utility in gene therapy for OS, particularly in combination with chemotherapeutic agents.

DOI PubMed

Involvement of splicing factor-1 in beta-catenin/T-cell factor-4-mediated gene transactivation and pre-mRNA splicing

Miki Shitashige, Yasuyoshi Naishiro, Masashi Idogawa, Kazufumi Honda, Masaya Ono, Setsuo Hirohashi, Tesshi Yamada

GASTROENTEROLOGY ( W B SAUNDERS CO-ELSEVIER INC ) 132 ( 3 ) 1039 - 1054 2007年03月 [査読有り]

Background & Aims: beta-Catenin is the downstream effector of the Wnt signaling pathway and is involved in the process of colorectal carcinogenesis. However, it is still uncertain whether P-catenin exerts its oncogenic function solely by coactivating the target genes of T-cell factor-4 (TCF4). We previously reported that the beta-catenin/TCF4 complex contains several classes of RNA-binding proteins and regulates the premessenger RNA splicing reaction, but the identity of the exact effector molecule downstream of the beta-catenin/TCF4 complex has not been established. Methods: Using isotope-coded affinity tagging and mass spectrometry, we examined more than 4000 peptides derived from colorectal cancer cells and identified that splicing factor-1 (SF1) was one of the proteins whose expression is regulated by the beta-catenin/TCF4 complex. Results: The expression of SF1 was found to be correlated with the differentiation status of intestinal epithelial cells and inversely correlated with tumorigenesis. Immunoprecipitation and immunofluorescence microscopy revealed that SF1 was a complex, and beta-catenin-evoked gene transactivation and cell proliferation were negatively regulated by SF1 complementary DNA transfection. SF1 was essential for the induction of alternative splicing by the beta-catenin/TCF4 complex, and SF1 complementary DNA transfection induced known cancer-related splice variants, such as Wnt-induced secreted protein-1v and fibroblast growth factor receptor-3-ATII. Conclusions: The beta-catenin/TCF4 complex regulates the level of SF1 protein expression, and, conversely, SF1 interacts with the complex and regulates its gene transactivation and premessenger RNA splicing activities. Identification of the interaction may shed light on a novel aspect of the Writ signaling pathway.

DOI PubMed

Ku70 and poly(ADP-ribose) polymerase-1 competitively regulate beta-catenin and T-cell factor-4-mediated gene transactivation: Possible linkage of DNA damage recognition and Wnt signaling

Masashi Idogawa, Mitsuko Masutani, Miki Shitashige, Kazufumi Honda, Takashi Tokino, Yasuhisa Shinomura, Kohzoh Imai, Setsuo Hirohashi, Tesshi Yamada

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 67 ( 3 ) 911 - 918 2007年02月 [査読有り]

担当区分：筆頭著者

Formation of the T-cell factor-4 (TCF-4) and beta-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and beta-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of beta-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed beta-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and beta-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and beta-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling.

DOI PubMed

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年12月 [査読有り]

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年09月

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年09月

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年09月

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年09月

β-Catenin interacts with the FUS proto-oncogene product and regulates pre-mRNA splicing

Satoshi Sato, Masashi Idogawa, Kazufumi Honda, Gen Fujii, Hisashi Kawashima, Kouji Takekuma, Akinori Hoshika, Setsuo Hirohashi, Tesshi Yamada, Tesshi Yamada

Gastroenterology ( W B SAUNDERS CO-ELSEVIER INC ) 129 ( 4 ) 1225 - 1236 2005年10月 [査読有り]

Background & Aims: β-Catenin is a downstream effector of the Wnt signaling pathway and is believed to exert its oncogenic function by activating T-cell factor (TCF)/lymphoid enhancer factor (LEF) family transcriptional factors. However, it is still uncertain whether the diverse effects of β-catenin are caused solely by aberrant gene transactivation. In this study, we used a proteomics approach to obtain further insight into the functional properties of nuclear β-catenin. Methods: The protein assembly of a native β-catenin-containing complex in nuclear extracts from a colorectal cancer cell line, DLD-1, was identified using immunoprecipitation and mass spectrometry. Results: β-Catenin physically interacted with fusion (FUS)/translocated in liposarcoma (TLS) and various RNA-binding proteins. The expression of FUS/TLS was closely associated with the accumulation of β-catenin and with the undifferentiated status of intestinal epithelial cells. The transient transfection of FUS suppressed β-catenin-evoked gene transactivation of TCF/LEF, and β-catenin transfection affected the splicing pattern of the E1A minigene and induced a novel splicing variant of estrogen receptor (ER)-β exerting a dominant-negative activity. Conclusions: Human cancer expresses a large variety of alternatively spliced messenger RNA (mRNA), but the precise molecular mechanisms responsible for cancer-related alternative splicing are largely unknown. In this study, we demonstrated the interaction of β-catenin with FUS/TLS and other RNA-binding proteins involved in the regulation of pre-mRNA splicing. Certain mRNA splicing abbreviations seen in human cancers may be induced by the activation of the Wnt signaling pathway. © 2005 by the American Gastroenterological Association.

DOI PubMed J-GLOBAL

E-cadherin regulates the association between β-catenin and actinin-4

Yasuharu Hayashida, Kazufumi Honda, Masashi Idogawa, Yoshinori Ino, Masaya Ono, Akihiko Tsuchida, Tatsuya Aoki, Setsuo Hirohashi, Tesshi Yamada, Tesshi Yamada

Cancer Research ( AMER ASSOC CANCER RESEARCH ) 65 ( 19 ) 8836 - 8845 2005年10月 [査読有り]

The E-cadherin/catenin system acts as an invasion suppressor of epithelial malignancies. This invasion suppressive activity seems be mediated not only by the cell adhesive activity of E-cadherin but by other undetermined signaling pathways elicited by β-catenin. In fact, cancer cells that have infiltrated the stroma reduce the expression of E-cadherin and accumulate β-catenin. We attempted to identify the alternative partner proteins that make complexes with β-catenin in the absence of E-cadherin. An ∼100-kDa protein was constantly coimmunoprecipitated with β-catenin from SW480 colorectal cancer cells, which lack the expression of E-cadherin, and was identified as actinin-4 by mass spectrometry. Transfection of E-cadherin cDNA suppressed the association between β-catenin and actinin-4. Inhibition of E-cadherin by RNA interference transferred the β-catenin and actinin-4 proteins into the membrane protrusions of DLD-1 cells. Immunofluorescence histochemistry of clinical colorectal cancer specimens showed that the β-catenin and actinin-4 proteins were colocalized in colorectal cancer cells infiltrating the stroma. We reported previously that over-expression of actinin-4 induces cell motility and specifically promotes lymph node metastasis by colorectal cancer. The association between β-catenin and actinin-4 and its regulation by E-cadherin may represent a novel molecular link connecting cell adhesion and motility. Shutting down the signals mediating this association may be worth considering as a therapeutic approach to cancer invasion and metastasis. ©2005 American Association for Cancer Research.

DOI PubMed J-GLOBAL

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年09月

Poly(ADP-ribose) polymerase-1 is a component of the oncogenic T-cell factor-4/beta-catenin complex

M Idogawa, T Yamada, K Honda, S Sato, K Imai, S Hirohashi

GASTROENTEROLOGY ( W B SAUNDERS CO ) 128 ( 7 ) 1919 - 1936 2005年06月 [査読有り]

担当区分：筆頭著者

Background & Aims: T-cell factor (TCF)-4 regulates a certain set of genes related to growth and differentiation of intestinal epithelial cells. Aberrant transactivation of these TCF-4-regulated genes by beta-catenin protein plays a crucial role in early intestinal carcinogenesis, and the transcriptional machinery of the TCF-4/beta-catenin complex is likely to contain targets for molecular therapy. We explored the molecular composition of the TCF-4/beta-catenin transcriptional complex by means of proteomics. Methods & Results: A protein of approximately 112 kilodaltons was consistently coimmunoprecipitated with FLAG-tagged TCF-4 transiently expressed in HEK293 cells, and the protein was identified by mass spectrometry as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 physically interacted with TCF-4 and augmented the transcriptional activity of the beta-catenin/TCF-4 complex. Knockdown of PARP-1 by RNA interference significantly suppressed both transcriptional activity and proliferation by colorectal cancer cells. Auto-polyADP-ribosylation of the PARP-1 protein induced by DNA damage inhibited the functional interaction of PARP-1 with TCF-4. PARP-1 was overexpressed in the intestinal adenomas of patients with familial adenomatous polyposis and multiple intestinal polyposis mice. The expression of PARP-1 was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells. Conclusions: In this study, we identified PARP-1 as a novel coactivator of the beta-catenin/TCF-4 complex. Although PARP-1 has been believed to play a protective role against carcinogenesis, these expression patterns and functional properties of PARP-1 were highly suggestive of its participation in early colorectal carcinogenesis.

DOI PubMed J-GLOBAL

Morphological and transcriptional responses of untransformed intestinal epithelial cells to an oncogenic β-catenin protein

Yasuyoshi Naishiro, Tesshi Yamada, Masashi Idogawa, Masashi Idogawa, Kazufumi Honda, Mizuho Takada, Tadashi Kondo, Kohzoh Imai, Setsuo Hirohashi

Oncogene ( NATURE PUBLISHING GROUP ) 24 ( 19 ) 3141 - 3153 2005年04月 [査読有り]

Aberrant transactivation of a certain set of target genes by the β-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor complexes has been implicated in the process of intestinal epithelial cells entering early colorectal carcinogenesis. A rat intestinal epithelial cell line IEC6 became elongated, extended protrusions at cell periphery, and increased stress fibers and focal contacts upon the induction of β-catenin protein stabilized by deletion of the N-terminal glycogen synthase kinase-3β (GSKβ) phosphorylation sites (β-catenin ΔN89). We used the GeneChip™ oligonucleotide microarray system to examine approximately 24 000 genes and identified 13 genes whose expression was altered during the course of this morphological transformation. Those genes included known negative regulators of the Wnt signaling pathway, Sfrp4 and Axin2; extracellular matrix and related molecule, Hxb and Crtl1; cell adhesion and cytoskeletal proteins, Podxl, Igaf4, and Itab6; and molecules involved in the insulin and insulin-like growth factor (IGF) signaling pathways, Enpp1, Igfbp2, and Sgk. We report the finding that insulin-like growth factor-binding protein-2 (IGFBP2) is a direct target gene of the β-catenin and TCF/LEF complexes. The IGFBP2 protein interacts with integrins. Disruption of the multigene network system regulating cell adhesion and cytoskeleton may be crucial in the initiation of colorectal carcinogenesis. © 2005 Nature Publishing Group All rights reserved.

DOI PubMed J-GLOBAL

Actinin-4 increases cell motility and promotes lymph node metastasis of colorectal cancer

K Honda, T Yamada, Y Hayashida, M Idogawa, S Sato, F Hasegawa, Y Ino, M Ono, S Hirohashi

GASTROENTEROLOGY ( W B SAUNDERS CO ) 128 ( 1 ) 51 - 62 2005年01月 [査読有り]

Background &Aims: Enhanced motility of cancer cells by remodeling of the actin cytoskeleton seems crucial in the process of cancer invasion and metastasis. We previously identified an actin-binding protein, actinin-4, as a new biomarker of cancer invasion and an indicator of prognosis for patients with breast cancer. However, its involvement in the mechanisms of cancer invasion and metastasis remains undetermined. The current study tested the role of actinin-4 in the motility and metastatic potential of colorectal cancer cells.Methods & Results: Quantitative immunofluorescence histochemistry showed that the expression level of the actinin-4 protein was increased in 73.1% (19/26) of the cases of colorectal cancer over the corresponding normal intestinal epithelium. The increased expression of actinin-4 was most significant in dedifferentiated cancer cells at the invasive front. A colorectal cancer cell clone capable of inducing actinin-4 using the tetracycline-regulatory system (designated DLD1 Tetoff ACTN-4) was established. Upon the induction of actinin-4, DLD1 Tet-off ACTN-4 cells spread filopodia and significantly increased their motility (P =.00027); actinin-4 protein was concentrated at the leading edges of these actin-rich podia. When injected into the mesocecum of severe combined immunodeficient mice, DLD1 Tet-off ACTN4 cells, but not the control cells, metastasized into regional mesenteric lymph nodes, resembling the behavior of clinical cancers. The expression of actinin-4 in focally dedifferentiated cancer cells at the invasive front was significantly correlated with the frequency of lymph node metastasis of colorectal cancer (P =.038). Conclusions: Actinin-4 actively increases cell motility and promotes lymph node metastasis of colorectal cancer.

DOI J-GLOBAL

Alternative splice variant of actinin-4 in small cell lung cancer

K Honda, T Yamada, M Seike, Y Hayashida, M Idogawa, T Kondo, Y Ino, S Hirohashi

ONCOGENE ( NATURE PUBLISHING GROUP ) 23 ( 30 ) 5257 - 5262 2004年07月 [査読有り]

Tumor-associated alternative RNA splicing has gained considerable attention. We identified a novel alternative splice variant RNA of actinin-4 in human small cell lung caner (SCLC). Expression of the splice variant was highly specific to SCLC cell lines (10/10), biopsies (3/3), and testis. The variant encoded a peptide with a three amino-acid change in exon 8, where the germline missense mutation takes place in familial focal segmental glomerulosclerosis (FSGS). The variant protein showed high affinity to filamentous actin polymers and was not localized with cortical actin. Alternatively spliced actinin-4 may be a new diagnostic marker of SCLC and a candidate target for selective therapy.

DOI PubMed J-GLOBAL

Overexpression of bad preferentially augments anoikis

M Idogawa, M Adachi, T Minami, H Yasui, K Imai

INTERNATIONAL JOURNAL OF CANCER ( WILEY-LISS ) 107 ( 2 ) 215 - 223 2003年11月 [査読有り]

担当区分：筆頭著者

BAD is a BH3-only protein, and its proapoptotic activity is negatively regulated by serine phosphorylation. Here, we show that overexpression of BAD preferentially augments anchorage loss-induced apoptosis (anoikis). Gene transfer-mediated BAD overexpression alone did not induce apoptosis in attached MDCK cells but strongly augmented apoptosis when cells were cultured in suspension. In contrast, overexpression of another BH3-only protein, BID, displayed much lower augmentation of anoikis, suggesting a preferential contribution of BAD to anoikis. During suspension culture, un-phosphorylated BAD was gradually increased and targeted to the mitochondria. Cotransfection of BAD with constitutively active Akt cDNA strongly inhibited this change. In contrast, the increase of un-phosphorylated BAD was not significantly inhibited by several phosphatase inhibitors or cotransfection with a dominant negative calcineurin cDNA, implying that the increase may be mainly due to a decrease of serine kinase activity, such as that of Akt. Similar results were observed in COS-7 cells, suggesting that BAD overexpression can increase sensitivity of anchorage-dependent cancer cells to anoikis. Thus, we propose that BAD can serve as a valuable gene therapeutic molecule to inhibit carcinoma progression. (C) 2003 Wiley-Liss, Inc.

DOI PubMed J-GLOBAL

Regulation of anoikis

Sakamoto H, Adachi M, Idogawa M, Nishimura S, Yasui H, Minami T, Imai K

Tumor Research ( 札幌医科大学 ) 36 1 - 6 2001年12月 [査読有り]

Normal epithelial and endothelial cells require attachment to extracellular matrix (ECM) proteins to grow or survive. In these anchorage-dependent cells, loss of interaction with the ECM proteins triggers apoptosis which is termed anoikis. Anoikis undoubtedly plays an essential role in the development and organization of normal tissues through its inhibitory effect on unfavorable cellular proliferation at inappropriate locations. In this regard, anoikis contributes to the maintenance of the physiological state. Importantly, disturbance of anoikis may allow cell proliferation at inappropriate sites and thus may be tightly linked to cancer development. Indeed, we have found that suppression of anoikis promotes peritoneal dissemination or metastasis of several carcinoma cells. These data imply that clarification of the molecular mechanism which regulates anoikis will, in turn, greatly help the regulation of cancer progression. Here we summarize recent advances in the field of anoikis regulation.

DOI CiNii

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