Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin

被引：58

作者：

Hayashi, I.

Takatori, S.

Urano, Y. ^{[2
]}

Miyake, Y. ^{[3
]}

Takagi, J. ^{[4
]}

Sakata-Yanagimoto, M. ^{[3
]}

Iwanari, H. ^{[2
,5
]}

Osawa, S.

Morohashi, Y.

Li, T. ^{[6
]}

Wong, P. C. ^{[6
]}

Chiba, S. ^{[3
]}

Kodama, T. ^{[2
]}

Hamakubo, T. ^{[2
]}

Tomita, T. ^{[1
,7
]}

Iwatsubo, T. ^{[7
,8
]}

机构：

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, Tokyo 1130033, Japan

[2] Univ Tokyo, Res Ctr Adv Sci & Technol, Dept Syst Biol & Med, Tokyo 1130033, Japan

[3] Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Clin & Expt Hematol, Tsukuba, Ibaraki, Japan

[4] Osaka Univ, Inst Prot Res, Lab Prot Synth & Express, Osaka, Japan

[5] Perseus Prote Inc, Tokyo, Japan

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[7] Japan Sci & Technol Agcy, Saitama, Japan

[8] Univ Tokyo, Grad Sch Med, Dept Neuropathol, Tokyo 1130033, Japan

来源：

ONCOGENE | 2012年 / 31卷 / 06期

基金：

日本学术振兴会;

关键词：

Notch; gamma-secretase; functional antibody; membrane protein; intramembrane cleavage; AMYLOID PRECURSOR PROTEIN; ACUTE LYMPHOBLASTIC-LEUKEMIA; BUDDED BACULOVIRUS; MEMBRANE-PROTEINS; BETA-APP; NOTCH; COMPLEX; PRESENILIN; CELLS; INHIBITION;

D O I：

10.1038/onc.2011.265

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by gamma-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the gamma-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active gamma-secretase complex on the cell surface, and inhibited the gamma-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the gamma-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of gamma-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant gamma-secretase activity and Notch signaling. Oncogene (2012) 31, 787-798; doi:10.1038/onc.2011.265; published online 4 July 2011

引用

页码：787 / 798

页数：12

共 46 条

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