Competitive Nuclear Export of Cyclin D1 and Hic-5 Regulates Anchorage Dependence of Cell Growth and Survival
Competitive Nuclear Export of Cyclin D1 and Hic-5 Regulates Anchorage Dependence of Cell Growth and Survival
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DOI：
10.1091/mbc.e08-04-0428
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Shibanuma, Motoko
中科院分区：
文献类型：
--
作者：
Mori, Kazunori;Hirao, Etsuko;Shibanuma, Motoko
细胞生长和存活的锚定依赖性是区分非转化细胞和转化细胞的关键特征。我们证明了锚定依赖性是由细胞周期蛋白D1的锚定依赖性核保留决定的，这是由黏附蛋白Hic-5调节的，Hic-5的crm1依赖性核输出抵消了细胞周期蛋白D1的核保留。接头蛋白PINCH与cyclin D1和Hic-5相互作用，并可能作为cyclin D1和Hic-5争夺CRM1的接口。在非贴壁细胞中，氧化还原敏感的Hic-5的核输出由于活性氧的增加而中断，细胞周期蛋白D1从细胞核输出。当以活性氧不敏感的方式连续输出的Hic-5突变体导入细胞时，细胞周期蛋白D1在非贴壁条件下保留在细胞核中，并且大量细胞逃脱了生长停滞或凋亡。有趣的是，激活的ras实现了主要的cyclin D1核定位，从而在非贴壁细胞中生长。我们报告了一个细胞生长和存活依赖于锚定的故障安全系统。
Anchorage dependence of cell growth and survival is a critical trait that distinguishes nontransformed cells from transformed cells. We demonstrate that anchorage dependence is determined by anchorage-dependent nuclear retention of cyclin D1, which is regulated by the focal adhesion protein, Hic-5, whose CRM1-dependent nuclear export counteracts that of cyclin D1. An adaptor protein, PINCH, interacts with cyclin D1 and Hic-5 and potentially serves as an interface for the competition between cyclin D1 and Hic-5 for CRM1. In nonadherent cells, the nuclear export of Hic-5, which is redox-sensitive, was interrupted due to elevated production of reactive oxygen species, and cyclin D1 was exported from the nucleus. When an Hic-5 mutant that was continuously exported in a reactive oxygen species-insensitive manner was introduced into the cells, cyclin D1 was retained in the nucleus under nonadherent conditions, and a significant population of cells escaped from growth arrest or apoptosis. Interestingly, activated ras achieved predominant cyclin D1 nuclear localization and thus, growth in nonadherent cells. We report a failsafe system for anchorage dependence of cell growth and survival.