Morgana/chp-1, a ROCK Inhibitor Involved in Centrosome Duplication and Tumorigenesis
Morgana/chp-1, a ROCK Inhibitor Involved in Centrosome Duplication and Tumorigenesis
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DOI：
10.1016/j.devcel.2009.12.020
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发表时间：
2010-03-16
影响因子：
11.8
通讯作者：
Brancaccio, Mara
中科院分区：
文献类型：
--
作者：
Ferretti, Roberta;Palumbo, Valeria;Brancaccio, Mara
中心体异常导致基因组不稳定，是许多癌细胞的共同特征。在这里，我们证明了moganA/CHP-1的突变导致果蝇和小鼠的中心体扩增和致死性，并且苍蝇的中心体表型完全被mogana的人类同源基因拯救。在小鼠细胞中，MOGANA与Hsp90、ROCK I和ROCK II形成复合体，并直接与ROCK II结合。MOGANA下调促进ROCK II与核磷蛋白(NPM)之间的相互作用，导致ROCK II激酶活性增加，从而导致中心体扩增。MOGANA(+/-)原代细胞和小鼠对肿瘤转化的敏感性增加。此外，肿瘤组织阵列组织化学分析显示，在很大一部分乳腺癌和肺癌中，摩尔加纳表达不足。因此，MOGANA/CHP-1似乎既能防止中心体扩增，又能阻止肿瘤的发生。
Centrosome abnormalities lead to genomic instability and are a common feature of many cancer cells. Here we show that mutations in morgana/chp-1 result in centrosome amplification and lethality in both Drosophila and mouse, and that the fly centrosome phenotype is fully rescued by the human ortholog of morgana. In mouse cells, morgana forms a complex with Hsp90 and ROCK I and II, and directly binds ROCK II. Morgana downregulation promotes the interaction between ROCK II and nucleophosmin (NPM), leading to an increased ROCK II kinase activity, which results in centrosome amplification. morgana(+/-) primary cells and mice display an increased susceptibility to neoplastic transformation. In addition, tumor tissue array histochemical analysis revealed that morgana is underexpressed in a large fraction of breast and lung human cancers. Thus, morgana/chp-1 appears to prevent both centrosome amplification and tumorigenesis.