Analysis for a new mechanism of neoplastic cell transformation through the centrosome control with MT1-MMP

MT1-MMP 中心体控制肿瘤细胞转化新机制分析

• 批准号: 23650592
• 负责人: MIKI Yoshio
• 金额: $ 2.33万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23650592/
• 关键词: ゲノム安定性; 発がん; がん抑制遺伝子; 乳がん; MT1-MMP; BRCA2; 中心体

BRCA2 is a multifunctional tumor suppressor protein with critical roles in DNA repair, replication, centrosome amplification, and cytokinesis. We previously identified the complexes of BRCA2 and membrane type-1 matrix metalloproteinase (MT1-MMP). In addition, we found the cleaved BRCA2 by MT1-MMP in cancer cells. To examine the role of the cleaved BRCA2 fragments, we generated cleavage-site-directed antibodies, which specifically recognize each of the fragments of BRCA2 (N-BRCA2 or C-BRCA2). Immunofluorescence analysis revealed that C-BRCA2 localizes to discrete nuclear foci. We measured the fluorescence intensity of the wild-type BRCA2 and C-BRCA2 nuclear foci in HeLa cells exposed to 10 Gy of ionizing radiation at several time points after irradiation. Interestingly, the intensity of wild-type BRCA2 foci was stronger near thenuclear envelope compared with the central part, but the intensity of cleaved C-BRCA2 foci was distributed evenly in the nucleus after irradiation. We suggest that BRCA2 is a cleavage target of MT1-MMP and that cleaved C-BRCA2 may play an important role in HRand breast oncogenesis.

BRCA 2是一种多功能肿瘤抑制蛋白，在DNA修复、复制、中心体扩增和胞质分裂中起关键作用。我们先前鉴定了BRCA 2和膜型1基质金属蛋白酶（MT 1-MMP）的复合物。此外，我们发现在癌细胞中MT 1-MMP切割BRCA 2。为了检查切割的BRCA 2片段的作用，我们产生了切割位点定向抗体，其特异性识别BRCA 2的每个片段（N-BRCA 2或C-BRCA 2）。免疫荧光分析显示，C-BRCA 2定位于离散的核灶。我们在照射后的几个时间点测量了暴露于10戈伊电离辐射的HeLa细胞中野生型BRCA 2和C-BRCA 2核灶的荧光强度。有趣的是，照射后野生型BRCA 2灶在核膜附近的强度较中心强，而裂解的C-BRCA 2灶在核内的强度分布较均匀。我们认为BRCA 2是MT 1-MMP的切割靶点，切割的C-BRCA 2可能在HR和乳腺癌发生中起重要作用。

项目成果

Prospective randomized phase II study determines the clinical usefulness of genetic biomarkers for sensitivity to primary chemotherapy with paclitaxel in breast cancer

• DOI: 10.1111/j.1349-7006.2010.01740.x
• 发表时间: 2011-01
• 期刊: Cancer Science
• 影响因子: 5.7
• 作者: Yoshinori Ito;K. Nagasaki;Y. Miki;T. Iwase;F. Akiyama;M. Matsuura;R. Horii;M. Makita;N. Tokudome;M. Ushijima;M. Yoshimoto;S. Takahashi;T. Noda;K. Hatake

BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2.

• DOI: 10.1158/0008-5472.can-10-0030
• 发表时间: 2011
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Hui-Feng Wang;K. Takenaka;A. Nakanishi;Y. Miki

BRCA2の新規機能と合成致死理論に基づく新規乳癌治療法開発の可能性

基于BRCA2的新功能和综合致死理论开发新的乳腺癌治疗方法的可能性

• 发表时间: 2012
• 作者: 西田満;喬森;宮本真理;山田真紀子;大谷浩;Christine Hartmann;西中村隆一;南康博;三木義男,中西啓
• 通讯作者: 三木義男,中西啓

Hereditary breast/ovarian cancer -New development of the molecular diagnosis and treatment-遺伝性乳がん・卵巣がん症候群-分子診断・治療の新たな展開

遗传性乳腺癌/卵巢癌-分子诊断与治疗新进展

• 发表时间: 2012
• 作者: Deraz;E. M.;Kudo;Y.;Yoshida;M.;Obayashi;M.;Tsunematsu;T.;Tani;H.;Siriwardena;S.;Keikhaee;M. R.;Qi;G.;Iizuka;S.;Ogawa;I.;Campisi;G.;Lo Muzio;L.;Abiko;Y.;Kikuchi;A.;Takata;T;尾崎充彦;三木義男,中西啓
• 通讯作者: 三木義男,中西啓

遺伝性乳がん卵巣がんの現状 問題点と展望 遺伝性乳がん原因遺伝子BRCA2の新規機能と新たな治療法開発の試み．

遗传性乳腺癌和卵巢癌的现状：问题与展望遗传性乳腺癌致病基因BRCA2的新功能并尝试开发新的治疗方法。

• 发表时间: 2012
• 作者: Endo;M;三木 義男
• 通讯作者: 三木 義男