Faculty Profiles - SAKAGUCHI Masakiyo

MISC - SAKAGUCHI Masakiyo

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C型ボツリヌス毒素変換ファージのゲノム情報を基盤とした偽溶原性メカニズムの解析

阪口義彦, OLIVA Maria A, MARTIN‐GALIANO Antonio J, ANDREU Jose M, 阪口政清, 内山淳平, 小椋義俊, 山本由弥子, 鈴木智典, 織田華絵, 津田千秋, 松崎茂展, 林哲也, 小熊惠二

日本分子生物学会年会プログラム・要旨集(Web) 35th WEB ONLY 3W3III-2 2012

TRAF6とSARM1によるPINK1のユビキチン化はマイトファジーの誘導に必須である

村田等, 阪口政清, 片岡健, HUH Nam‐ho

日本分子生物学会年会プログラム・要旨集(Web) 35th 4P-0506 (WEB ONLY) 2012

多機能受容体RAGEの下流信号伝達機構の解明(TIRAP is a critical transducer of RAGE-mediated inflammatory signaling)

阪口政清, 村田等, 山本健一, 阪口義彦, 本山晃, 日比野利彦, 片岡健, 許南浩

日本癌学会総会記事 70回 225 - 225 2011.9

PINK1発現抑制によるミトコンドリア機能不全はREIC/Dkk-3のアポトーシス誘導効果を増強する(Mitochondrial malfunction by PINK1 knockdown augments apoptosis induced by adenovirus carrying REIC/Dkk-3)

村田等, 金玉, 阪口政清, 片岡健, 許南浩

日本癌学会総会記事 70回 51 - 51 2011.9

S100A7による骨肉腫細胞の遊走・浸潤の多機能受容体RAGEを介した制御機構(Promotion of migration and invasion of osteosarcoma cells by S100A7 through RAGE)

片岡健, 阪口政清, 小野智之, 森下美加, 山本健一, 村田等, 許南浩

日本癌学会総会記事 70回 79 - 79 2011.9

Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1

Kazuhiko Ochiai, Masami Watanabe, Hideo Ueki, Peng Huang, Yasuyuki Fujii, Yasutomo Nasu, Hirofumi Noguchi, Takeshi Hirata, Masakiyo Sakaguchi, Nam-ho Huh, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 412 ( 2 ) 391 - 395 2011.8

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

REIC/Dkk-3 is a member of the Dickkopf family proteins known as Wnt-antagonists, and REIC/Dkk-3 expression is downregulated in a broad range of cancer types. REIC/Dkk-3 acts as a tumor suppressor in multiple cancer cell lines by inducing apoptosis through endoplasmic reticulum (ER) stress signaling. However, the intracellular interaction partners of REIC/Dkk-3 have not been fully elucidated. By employing yeast two-hybrid screening, we identified the human dynein light chain, Tctex-1, as a novel interaction partner of REIC/Dkk-3. We further disclosed that the interaction involves the 136-157 amino acid region of REIC/Dkk-3 by using the mammalian two-hybrid system. Interestingly, this binding region of REIC/Dkk-3 with Tctex-1 contains an amino acid sequence motif [-(E) under bar -X-(G) under bar-(R) under bar-(R) under bar -X-(H) under bar-] which was previously reported as the Tctex-1 binding domain of dynein intermediate chain (DIC). Immunocytochemistry demonstrated that both REIC/Dkk-3 and Tctex-1 were localized around the ER of human fibroblasts, and the similar distribution pattern of the proteins suggests that their interaction occurs around the ER. This is the first study showing the interaction of a Dickkopf family protein with a dynein motor complex protein. The link between REIC/Dkk-3 and Tctex-1 may be of significance for understanding the molecular functions of the proteins in ER stress signaling and intracellular dynein motor dynamics, respectively. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.07.109

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Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma

Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Masakiyo Sakaguchi, Takuya Fukazawa, Junichi Soh, Hiroaki Asano, Tsuyoshi Ueno, Takayuki Muraoka, Hiromasa Yamamoto, Yasutomo Nasu, Takumi Kishimoto, Harvey I. Pass, Hideki Matsui, Nam-ho Huh, Shinichiro Miyoshi

CLINICAL CANCER RESEARCH 17 ( 15 ) 4965 - 4974 2011.8

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.
Experimental Design: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.
Results: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.
Conclusions: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. Clin Cancer Res; 17(15); 4965-74. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-3040

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TIRAP, an Adaptor Protein for TLR2/4, Transduces a Signal from RAGE Phosphorylated upon Ligand Binding

Masakiyo Sakaguchi, Hitoshi Murata, Ken-ichi Yamamoto, Tomoyuki Ono, Yoshihiko Sakaguchi, Akira Motoyama, Toshihiko Hibino, Ken Kataoka, Nam-ho Huh

PLOS ONE 6 ( 8 ) 23132 - 23132 2011.8

Language：English Publisher：PUBLIC LIBRARY SCIENCE

The receptor for advanced glycation end products (RAGE) is thought to be involved in the pathogenesis of a broad range of inflammatory, degenerative and hyperproliferative diseases. It binds to diverse ligands and activates multiple intracellular signaling pathways. Despite these pivotal functions, molecular events just downstream of ligand-activated RAGE have been surprisingly unknown. Here we show that the cytoplasmic domain of RAGE is phosphorylated at Ser391 by PKCf upon binding of ligands. TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE. Our findings indicate that functional interaction between RAGE and TLRs coordinately regulates inflammation, immune response and other cellular functions.

DOI： 10.1371/journal.pone.0023132

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Multiple functions of PINK1 at different intracellular locations Beyond neurodegenerative diseases

Hitoshi Murata, Masakiyo Sakaguchi, Ken Kataoka, Nam-ho Huh

CELL CYCLE 10 ( 10 ) 1518 - 1519 2011.5

Markedly elevated serum levels of calcium-binding S100A8/A9 proteins in psoriatic arthritis are due to activated. monocytes/macrophages

Seiko Aochi, Kazuhide Tsuji, Masakiyo Sakaguchi, Namho Huh, Tatsuya Tsuda, Kiyofumi Yamanishi, Mayumi Komine, Keiji Iwatsuki

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 64 ( 5 ) 879 - 887 2011.5

Language：English Publisher：MOSBY-ELSEVIER

Background: Serum levels of S100A8/A9 may correlate with disease activity in psoriasis.
Objective: We sought to elucidate the association of serum levels of S100A8/A9 heterodimers with the clinical subtypes of psoriasis and the major cell source.
Methods: Serum samples were collected from patients with psoriasis vulgaris (n = 30), psoriatic arthritis (PA) (n = 16),. pustular psoriasis (n = 24), and atopic dermatitis (n = 14) and from healthy control subjects (n = 21). Serum concentrations of S100A8/A9 were measured, and the expression levels were examined in psoriatic lesions. The messenger RNA levels were quantified in circulating monocytes and neutrophils.
Results: Serum levels of S100A8/A9 were significantly increased in all subtypes of psoriasis as compared with healthy controls and atopic dermatitis. Among the psoriatic subtypes, PA and pustular psoriasis showed remarkably high concentrations of S100A8/A9 heterodimers. The higher serum levels were associated with the presence of articular symptoms, but not significantly correlated with body surface areas of psoriatic lesions. S100A8 was expressed by both keratinocytes and infiltrating mononuclear cells, whereas S100A9 was predominantly expressed by neutrophils. The expression levels of S100A8 and S100A9 messenger RNA in monocytes were increased by approximately 2.25- and 1.91-fold in PA, respectively, whereas no significant increase was observed in psoriasis vulgaris and pustular psoriasis.
Limitations: Difficulty in acquisition of clinical and laboratory samples in untreated patients, and of a sufficient number of subjects, were limitations.
Conclusions: Although serum levels of S100A8/A9 were increased in all types of psoriasis examined, patients with PA had higher levels of S100A8/A9, probably because of an activated monocyte/macrophage system. (J Am Acad Dermatol 2011;64:879-87.)

DOI： 10.1016/j.jaad.2010.02.049

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Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma

Swe Swe Than, Ken Kataoka, Masakiyo Sakaguchi, Hitoshi Murata, Fernando Abarzua, Chika Taketa, Gang Du, Masakazu Yashiro, Kazuyoshi Yanagihara, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

ONCOLOGY REPORTS 25 ( 4 ) 989 - 995 2011.4

Language：English Publisher：SPANDIDOS PUBL LTD

Expression levels of the novel tumor suppressor gene REIC/Dkk-3 are reduced in many human cancers. We have previously showed that an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) induced apoptosis of cancer cells selectively and exerted bystander antitumor effects via ER stress. We examined possible effects of Ad-REIC in a peritoneal dissemination model of scirrhous gastric carcinoma (SGC). Among various types of gastric cancer, SGC continues to be associated with the worst prognosis due to a high incidence of metastases in the peritoneal cavity. We found that a single intraperitoneal injection of Ad-REIC suppressed tumor dissemination and disease progression. Immunomodulation by Ad-REIC led to recruitment of natural killer cells inside tumor nodules. We conclude that Ad-REIC gene therapy may be a potential tool in combinatorial approaches to achieve curative effects in SGC.

DOI： 10.3892/or.2011.1149

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Identification of EMMPRIN as a novel receptor for S100A9: Its involvement in melanoma metastasis

T. Hibino, S. Miyamoto, M. Sakaguchi, A. Motoyama, M. Yamamoto, R. Tsuboi, N. Huh

JOURNAL OF INVESTIGATIVE DERMATOLOGY 131 S126 - S126 2011.4

Expression of REIC/Dkk-3 in normal and hyperproliferative epidermis

Gang Du, Ken Kataoka, Masakiyo Sakaguchi, Fernando Abarzua, Swe Swe Than, Hiroyuki Sonegawa, Teruhiko Makino, Tadamichi Shimizu, Nam-Ho Huh

EXPERIMENTAL DERMATOLOGY 20 ( 3 ) 273 - 277 2011.3

Language：English Publisher：WILEY-BLACKWELL

Dickkopf (Dkk) family members are known as Wnt modulators involved in the development, cell growth/differentiation and cancer. REIC/Dkk-3, which does not interfere with Wnt signalling, has been proposed to be a tumor suppressor gene, but its physiological function has remained unclear. In this study, we analysed the expression of REIC/Dkk-3 in normal interfollicular epidermis (IFE) and hyperproliferative epidermis. REIC/Dkk-3 was expressed in human and mouse IFE, being localized at the interface of upper spinous layer and granular layer. Skin cancer cell lines lost REIC/Dkk-3 expression as reported previously. When we analysed patient samples, REIC/Dkk-3 expression was down-regulated in the hyperproliferative epidermis including skin cancers and non-cancerous proliferative diseases. REIC/Dkk-3 expression was also suppressed in the regenerative and inflammative epidermis of model mice. These findings will certainly contribute to the extension of studies on REIC/Dkk-3.

DOI： 10.1111/j.1600-0625.2010.01244.x

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REIC/Dkk-3の扁平上皮における発現とその制御因子の探索

片岡健, 阪口政清, 杜剛, 前原奈都美, 村田等, 許南浩

組織培養研究 30 ( 1 ) 99 - 99 2011.3

A New Cytosolic Pathway from a Parkinson Disease-associated Kinase, BRPK/PINK1 ACTIVATION OF AKT VIA MTORC2

Hitoshi Murata, Masakiyo Sakaguchi, Yu Jin, Yoshihiko Sakaguchi, Jun-ichiro Futami, Hidenori Yamada, Ken Kataoka, Nam-ho Huh

JOURNAL OF BIOLOGICAL CHEMISTRY 286 ( 9 ) 7182 - 7189 2011.3

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Accumulating evidence indicates that dysfunction of mitochondria is a common feature of Parkinson disease. Functional loss of a familial Parkinson disease-linked gene, BRPK/PINK1 (PINK1), results in deterioration of mitochondrial functions and eventual neuronal cell death. A mitochondrial chaperone protein has been shown to be a substrate of PINK1 kinase activity. In this study, we demonstrated that PINK1 has another action point in the cytoplasm. Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. Rictor, a specific component of mTORC2, was phosphorylated by overexpression of PINK1. Furthermore, overexpression of PINK1 enhanced cell motility. These results indicate that PINK1 exerts its cytoprotective function not only in mitochondria but also in the cytoplasm through activation of mTORC2.

DOI： 10.1074/jbc.M110.179390

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正常皮膚におけるREIC/Dkk‐3の発現制御因子の検索

前原奈都美, 片岡健, DU Gang, 村田等, 山本健一, 阪口政清, HUH Nam‐Ho

日本分子生物学会年会プログラム・要旨集(Web) 34th 1P-0254 (WEB ONLY) 2011

S100タンパク質受容体の結合解析

森下美加, 村田等, 山本健一, 片岡健, 阪口政清, HUH Nam‐Ho

日本分子生物学会年会プログラム・要旨集(Web) 34th 4P-0293 (WEB ONLY) 2011

A novel tumor suppressor, REIC/Dkk-3 gene identified by our in vitro transformation model of normal human fibroblasts works as a potent therapeutic anti-tumor agent

Masakiyo Sakaguchi, Nam-Ho Huh, Masayoshi Namba

Advances in Experimental Medicine and Biology 720 209 - 215 2011

Language：English

Reduced Expression in Immortalized Cell (REIC) was cloned by subtractive hybridization method as a gene whose expression is reduced in many human immortalized and neoplastic tumor cells. The REIC, when over-expressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on a wide variety of human cancers through a mechanism triggered by ER-stress-mediated JNK activation. In addition to this direct effect on cancer cells, Ad-REIC exerted another cytotoxicity on human cancers, an indirect host-mediated effect due to overproduction of IL-7 by mis-targeted normal cells. This "one-bullet two-arms" finding may lead to a powerful new therapeutic approach to the treatment of human cancers. © 2011 Springer Science+Business Media, LLC.

DOI： 10.1007/978-1-4614-0254-1_17

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Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development

Kai Zhang, Masami Watanabe, Yuji Kashiwakura, Shun-Al Li, Kohei Edamura, Peng Huang, Ken Yamaguchi, Yasutomo Nasu, Yasuyuki Kobayashi, Masakiyo Sakaguchi, Kazuhiko Ochiai, Hiroshi Yamada, Kohji Takei, Hideo Ueki, Nam-Ho Huh, Ming Li, Haruki Kaku, Yanqun Na, Hiromi Kumon

INTERNATIONAL JOURNAL OF ONCOLOGY 37 ( 6 ) 1495 - 1501 2010.12

Language：English Publisher：SPANDIDOS PUBL LTD

The tumor suppressor REIC/Dkk-3 is a secretory protein which was originally identified to be downregulated in human immortalized cells In the present study, we investigated the expression pattern of REIC/Dkk-3 in various cell types to characterize its physiological functions We first examined the expression level of REIC/Dkk-3 in a broad range of cancer cell types and confirmed that it was significantly downregulated in all of the cell types We also examined the tissue distribution pattern in a variety of normal mouse organs Ubiquitous REIC/Dkk-3 protein expression was observed in the organs The expression was abundant in the liver, heart and brain tissue, but was absent in the spleen and peripheral blood mononuclear cells The immunohistochemical analyses revealed that the subcellular localization of REIC/Dkk-3 had a punctate pattern around the nucleus, indicating its association with secretory vesicles In cancer cells stably transfected with REIC/Dkk-3 the protein was predominantly localized to the endoplasmic reticulum (ER) under observation with confocal microscopy Because REIC/ Dkk-3 was found to be abundantly expressed in the acinar epithelial cells of the mouse prostate, we analyzed the effects of recombinant REIC/Dkk-3 protein on the acinar morphogenesis of RWPE-1 cells, which are derived from human normal prostate epithelium Statistically significant acinar growth was observed in the culture condition with 10 mu g/m1 REIC/Dkk-3 protein, implicating the soluble form m prostatic acinar development Current results suggest that REIC/Dkk-3 may play a role in regulating the morphological process of normal tissue architecture through an autocrine and/or paracrine manner

DOI： 10.3892/ijo_00000802

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KLF11とKLF15によるUCP1の発現制御

山本健一, 阪口政清, 片岡健, 許南浩

日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 83回・33回 2P - 0822 2010.12

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MISC - SAKAGUCHI Masakiyo