Competitive nuclear export of cyclin D1 and Hic-5 regulates anchorage-dependence of cell growth and survival

由于细胞周期蛋白D1的致瘤性依赖于其亚细胞定位，其调控机制一直受到人们的密切关注。在这里，我们发现，细胞周期蛋白D1的核定位是锚定依赖性和调节的粘着斑蛋白，Hic-5，穿梭在细胞核内外通过CRM 1的输出系统，本地化细胞周期蛋白D1在细胞核中抵消细胞周期蛋白D1的核输出。在非贴壁细胞中，细胞周期蛋白D1从细胞核中积极输出，因为Hic-5的穿梭被活性氧（ROS）水平升高打断。相反，Hic-5的穿梭获得ROS的不敏感性，允许细胞周期蛋白D1的核定位和伴随的逃逸细胞的生长停滞或凋亡的非粘附细胞。感兴趣的是，激活的ras绕过了上述调节，并实现了主要的细胞周期蛋白D1的核定位和非贴壁细胞的锚定非依赖性生长。总之，细胞周期蛋白D1的一个新的分子方面，其核定位的锚定依赖性，已经出现;这种失调与肿瘤发生密切相关，允许锚定独立的细胞生长。

Because the oncogenicity of cyclin D1 depends on its subcellular localization, the regulatory mechanisms have been under intense investigation. Here we discovered that the nuclear localization of cyclin D1 was anchorage-dependent and regulated by a focal adhesion protein, Hic-5, shuttling in and out of the nucleus through the CRM1 export system, which localized cyclin D1 in the nucleus by counteracting the nuclear export of cyclin D1. In non-adherent cells, cyclin D1 was actively exported from the nucleus because the shuttling of Hic-5 was interrupted by an elevated level of reactive oxygen species (ROS). Conversely, shuttling of Hic-5 which acquired insensitivity to ROS allowed nuclear localization of cyclin D1 and a concomitant escape of cells from growth arrest or apoptosis in non-adherent cells. Of interest, activated ras circumvented the above regulation and achieved predominant nuclear localization of cyclin D1 and anchorage-independent growth in non-adherent cells. Together, a new molecular aspect of cyclin D1, the anchorage-dependency of its nuclear localization, has emerged; this deregulation is intimately associated with tumorigenesis, permitting anchorage-independent growth of cells.