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

细胞周期蛋白 D1 和 Hic-5 的竞争性核输出调节细胞生长和存活的贴壁依赖性

• 批准号: 20790263
• 负责人: KAZUNORI Mori
• 金额: $ 2.75万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20790263/
• 关键词: 足場依存性増殖; 非依存性増殖; サイクリンD1; Hic-5; 足場非依存性増殖; 足場依存性; cyclin D1; 活性酸素種

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.

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。

项目成果

Involvement of focal adhesion-nucleus shuttling protein, Hic-5 imregulation of cell growth/survival of cancer cells

粘着斑-核穿梭蛋白、Hic-5 对细胞生长/癌细胞存活的调节的参与

• 发表时间: 2009
• 作者: Toshihiko Yoshic;Kazunori Mori;Teisu Uchida;Hiroyuki Miyoshi;Fumihiro Ishikawa;Motoko Shibanuma
• 通讯作者: Motoko Shibanuma

活性化 ras による cyclin D1 核局在の接着依存性の喪失

激活的 ras 导致细胞周期蛋白 D1 核定位的粘附依赖性丧失

• 发表时间: 2008
• 作者: 森岡 一憲;外谷 陽介;野瀬 清;柴沼 質子
• 通讯作者: 柴沼 質子

細胞接着斑タンパク質Hic-5による接着応答性、細胞死誘導とがん細胞死制御の可能性

细胞粘附蛋白 Hic-5 的粘附反应性、细胞死亡诱导和癌细胞死亡控制的可能性

• 发表时间: 2008
• 作者: 溝手優子;森一憲;野瀬清;柴沼質子
• 通讯作者: 柴沼質子

Transactivation of the p21^<cipl> promoter by Hic-5, a focal adhesion protein, in response to disruption of cell-matrix interaction

Hic-5（一种粘着斑蛋白）对 p21^<cipl> 启动子的反式激活，响应细胞-基质相互作用的破坏

• 发表时间: 2009
• 作者: Kauznori Mori;Fumihiro Ishikawa;Kiyoshi Nose;Motoko
• 通讯作者: Motoko

足場依存性増殖制御に関わる細胞接着斑-核シャトルHic-5複合体によるcyclin D1核局在制御機構の解析

细胞粘着斑-核梭Hic-5复合物对细胞周期蛋白D1的核定位控制机制分析参与贴壁依赖性生长控制

• 发表时间: 2008
• 作者: 荒木裕理;森一憲;野瀬清;柴沼質子
• 通讯作者: 柴沼質子