BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2.
BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2.
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DOI：
10.1158/0008-5472.can-10-0030
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发表时间：
2011
期刊：
影响因子：
11.2
通讯作者：
Hui-Feng Wang;K. Takenaka;A. Nakanishi;Y. Miki
中科院分区：
文献类型：
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作者：
Hui-Feng Wang;K. Takenaka;A. Nakanishi;Y. Miki
BRCA2种系突变是遗传性乳腺癌和卵巢癌的主要原因。BRCA2除了在DNA损伤修复中发挥作用外，还在细胞质分裂、转录调节和癌细胞增殖中发挥重要作用。最近，我们报道了BRCA2定位于中心体和细胞核，中心体中BRCA2的功能障碍导致细胞分裂异常。在这里，我们确定了一个核仁磷酸化蛋白，核磷蛋白（NPM），作为一个新的brca2相关蛋白。我们还检测到BRCA2与Rho小GTPase的效应物ROCK2的结合。由于已知ROCK2在中心体上与NPM结合，这3种蛋白可能形成复合物。npm结合区位于BRCA2的639- 1000个氨基酸内。该BRCA2区域的外源表达导致中心体异常扩增和多核细胞的高频率。我们的研究结果表明，由BRCA2、NPM和ROCK2组成的复合体维持着中心体的数量完整性和精确的细胞分裂，这种调节的功能障碍可能参与了乳腺癌的肿瘤发生。
BRCA2 germline mutations account for the majority of heredity breast and ovarian cancer. Besides its role in DNA damage repair, BRCA2 also plays an important role in cytokinesis, transcription regulation, and cancer cell proliferation. Recently, we reported that BRCA2 localizes to centrosomes as well as nuclei and the dysfunction of BRCA2 in a centrosome causes abnormalities in cell division. Here, we identified a nucleolar phosphoprotein, nucleophosmin (NPM), as a novel BRCA2-associated protein. We also detected the binding of BRCA2 to ROCK2, an effector of Rho small GTPase. Because it is known that ROCK2 binds to NPM at centrosomes, these 3 proteins may form a complex. NPM-binding region was within amino acids 639-1,000 of BRCA2. Exogenous expression of this BRCA2 region resulted in aberrant centrosome amplification and a high frequency of multinucleated cells. Our results suggested that a complex consisting of BRCA2, NPM, and ROCK2 maintains the numerical integrity of centrosomes and accurate cell division and that dysfunction of this regulation might be involved in the tumorigenesis of breast cancer.