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的致癌性取决于其亚细胞定位，其调控机制一直处于深入研究之中。在这里，我们发现cyclin D1的核定位是锚定依赖性的，并受一个局点粘附蛋白Hic-5的调控，Hic-5通过CRM1输出系统进出细胞核，该系统通过抵消cyclin D1的核输出来将cyclin D1定位在细胞核中。在非贴壁细胞中，由于Hic-5的穿梭被活性氧（ROS）水平的升高打断，细胞周期蛋白D1被积极地从细胞核中输出。相反，对ROS不敏感的Hic-5的穿梭使细胞周期蛋白D1的核定位和非贴壁细胞中细胞从生长停滞或凋亡中逃逸。有趣的是，激活的ras绕过了上述调节，在非贴壁细胞中实现了cyclin D1的主要核定位和非锚定依赖性生长。总之，cyclin 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，允许细胞不依赖于锚定生长。

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.