Tomoko Nishimaki‐Mogami

National Institute of Health Sciences

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Norimasa Tamehiro

National Institute of Health Sciences

Mikihiko Naito

The University of Tokyo

Kazunari Kondo

National Institute of Health Sciences

Keiichiro Okuhira

Osaka University of Pharmaceutical Sciences

Mizuho Une

Hiroshima International University

Yoshiro Saito

National Institute of Health Sciences

Akihiko Hirose

National Institute of Health Sciences

Kôsuke Nakamura

National Institute of Health Sciences

Kazuhide Inoue

Kyushu University

Kimie Sai

SRM Institute of Science and Technology

Cooperative Institutions

National Institute of Health Sciences

129

The University of Tokyo

National Institute of Health Sciences

Kyoto University

Osaka University

Tohoku University

Tokyo Institute of Technology

Nagoya University

Japan Science and Technology Agency

Tokyo University of Science

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The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression

Journal of Pharmacological Sciences (2008)

Takuo Suzuki Norimasa Tamehiro Yoji Sato Tetsu Kobayashi Akiko Ishii‐Watabe

Farnesoid X receptor

Chenodeoxycholic acid

CYP8B1

Small heterodimer partner

10.1254/jphs.08006fp

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Citations (35)

The N-linked oligosaccharides at the amino terminus of human apoB are important for the assembly and secretion of VLDL

Journal of Lipid Research (2002)

Jelena Vukmirica Tomoko Nishimaki‐Mogami Khai Tran Jing Shan Roger S. McLeod

We determined the role of N-linked glycosylation of apolipoprotein B (apoB) in the assembly and secretion of lipoproteins using transfected rat hepatoma McA-RH7777 cells expressing human apoB-17, apoB-37, and apoB-50, three apoB variants with different ability to recruit neutral lipids. Substituting Asn residue with Gln at the single glycosylation site within apoB-17 (N¹⁵⁸) decreased its secretion efficiency to a level equivalent to that of wild-type apoB-17 treated with tunicamycin, but had little effect on its synthesis or intracellular distribution. When selective N-to-Q substitution was introduced at one or more of the five N-linked glycosylation sites within apoB-37 (N¹⁵⁸, N⁹⁵⁶, N¹³⁴¹, N¹³⁵⁰, and N¹⁴⁹⁶), secretion efficiency of apoB-37 from transiently transfected cells was variably affected. When all five N-linked glycosylation sites were mutated within apoB-37, the secretion efficiency and association with lipoproteins were decreased by >50% as compared with wild-type apoB-37. Similarly, mutant apoB-50 with all of its N-linked glycosylation sites mutagenized showed decreased secretion efficiency and decreased lipoprotein association in both d < 1.02 and d > 1.02 g/ml fractions. The inability of mutant apoB-37 and apoB-50 to associate with very low-density lipoproteins was attributable to impaired assembly and was not due to the limitation of lipid availability. The decreased secretion of mutant apoB-17 and apoB-37 was not accompanied by accumulation within the cells, suggesting that the proportion of mutant apoB not secreted was rapidly degraded. However unlike apoB-17 or apoB-37, accumulation of mutant apoB-50 was observed within the endoplasmic reticulum and Golgi compartments. These data imply that the N-glycans at the amino terminus of apoB play an important role in the assembly and secretion of lipoproteins containing the carboxyl terminally truncated apoB.

Tunicamycin

10.1194/jlr.m200077-jlr200

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Development of hybrid small molecules that induce degradation of estrogen receptor‐alpha and necrotic cell death in breast cancer cells

Cancer Science (2013)

Keiichiro Okuhira Yosuke Demizu Takayuki Hattori Nobumichi Ohoka Norihito Shibata

Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed a series of hybrid small molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser) that induces degradation of target proteins via ubiquitin-proteasome system. Here we report the activities of SNIPER(ER) that targets estrogen receptor alpha (ERα) for degradation. SNIPER(ER) induced degradation of ERα and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer cell line MCF-7. A proteasome inhibitor MG132 and siRNA-mediated downregulation of cIAP1 abrogated the SNIPER(ER)-induced ERα degradation, suggesting that the ERα is degraded by proteasome subsequent to cIAP1-mediated ubiquitylation. Intriguingly, after the ERα degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, a marker of necrosis, from the cells. Following the ERα degradation, reactive oxygen species (ROS) was produced in the SNIPER(ER)-treated MCF-7 cells, and an anti-oxidant N-acetylcysteine inhibited the necrotic cell death. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα-positive breast cancers.

Estrogen receptor alpha

Protein Degradation

10.1111/cas.12272

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Citations (121)

Genetic Variations and Haplotypes of ABCC2 Encoding MRP2 in a Japanese Population

Drug Metabolism and Pharmacokinetics (2008)

Kimie Sai Yoshiro Saito Masaya Itoda Hiromi Fukushima‐Uesaka Tomoko Nishimaki‐Mogami

Nonsynonymous substitution

10.2133/dmpk.23.139

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Citations (27)

Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor

Journal of Lipid Research (2004)

Tomoko Nishimaki‐Mogami Mizuho Une Tomofumi Fujino Yoji Sato Norimasa Tamehiro

Bile acid synthesis from cholesterol is tightly regulated via a feedback mechanism mediated by the farnesoid X receptor (FXR), a nuclear receptor activated by bile acids. Synthesis via the classic pathway is initiated by a series of cholesterol ring modifications and followed by the side chain cleavage. Several intermediates accumulate or are excreted as end products of the pathway in diseases involving defective bile acid biosynthesis. In this study, we investigated the ability of these intermediates to activate human FXR. In a cell-based reporter assay and coactivator recruitment assays in vitro, early intermediates possessing an intact cholesterol side chain were inactive, whereas 26- or 25-hydroxylated bile alcohols and C27 bile acids were highly efficacious ligands for FXR at a level comparable to that of the most potent physiological ligand, chenodeoxycholic acid. Treatment of HepG2 cells with these precursors repressed the rate-limiting cholesterol 7alpha-hydroxylase mRNA level and induced the small heterodimer partner and the bile salt export pump mRNA, indicating the ability to regulate bile acid synthesis and excretion. Because 26-hydroxylated bile alcohols and C27 bile acids are known to be evolutionary precursors of bile acids in mammals, our findings suggest that human FXR may have retained affinity to these precursors during evolution.

Farnesoid X receptor

Identification

10.1194/jlr.m400102-jlr200

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Citations (67)

新しい核内受容体配位子,ジゴキシゲニン,は肝臓X受容体の選択的拮抗薬である

Chemistry Letters (2017)

Oishi Haruka Yousuke TAKAOKA Tomoko Nishimaki‐Mogami Saito Hiroaki Ueda Minoru

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In vitro farnesoid X receptor ligand sensor assay using surface plasmon resonance and based on ligand-induced coactivator association