CRM1-mediated nuclear export determines the cytoplasmic localization of the antiapoptotic protein survivin
CRM1-mediated nuclear export determines the cytoplasmic localization of the antiapoptotic protein survivin
复制标题
DOI：
10.1006/excr.2002.5492
复制
发表时间：
2002-04-15
影响因子：
3.7
通讯作者：
Giaccone, G
中科院分区：
文献类型：
--
作者：
Rodríguez, JA;Span, SW;Giaccone, G
Survivin 是程序性细胞死亡负调节因子凋亡抑制剂 (IAP) 家族的成员，在人类肿瘤中经常过度表达。 Survivin 不仅参与细胞凋亡的调节，还已知在 GSM 期细胞周期进程的控制中发挥作用。生存素是一种主要以细胞周期依赖性方式表达的细胞质蛋白，但决定其核细胞质定位的机制尚未描述。在这项研究中，我们报告 Survivin 是一种核穿梭蛋白，通过 CRM1 依赖性途径从细胞核主动输出。 Survivin 的核输出独立于控制 G(2)/M 相变的其他穿梭蛋白的输出，例如细胞周期蛋白 B1 和 cdc25。生存素的羧基末端结构域对于其核输出来说既是必要的又是充分的，尽管该区域不包含功能性的富含亮氨酸的核输出信号。该区域氨基酸序列的差异决定了Survivin（在细胞质中）及其剪接变体Survivin-DeltaEx3（在细胞核中）的显着不同定位。 Survivin-DEx3 的羧基末端含有 Survivin 中不存在的二分核定位信号，该信号介导其强大的核积累。这些数据表明细胞核和细胞质之间的主动转运可能构成Survivin功能的重要调节机制。 (C) 2002 年爱思唯尔科学（美国）。
Survivin is a member of the inhibitor of apoptosis (IAP) family of negative regulators of programmed cell death that is frequently overexpressed in human tumors. Survivin is not only involved in the regulation of apoptosis, but is also known to play a role in the control of cell cycle progression at the GSM phase. Survivin is a predominantly cytoplasmic protein expressed in a cell cycle-dependent manner, but the mechanism(s) that determine its nuclear-cytoplasmic localization have not been described. In this study, we report that Survivin is a nuclear shuttling protein that is actively exported from the nucleus via the CRM1-dependent pathway. Nuclear export of Survivin is independent of the export of other shuttling proteins that control the G(2)/M phase transition, such as cyclin B1 and cdc25. The carboxy-terminal domain of Survivin is both necessary and sufficient for its nuclear export, although this region does not contain a functional leucine-rich nuclear export signal. Differences in the amino acid sequence of this region determine the dramatically different localization of Survivin (in the cytoplasm) and its splicing variant Survivin-DeltaEx3 (in the nucleus). The carboxy-terminal end of Survivin-DEx3 contains a bipartite nuclear localization signal, not present in Survivin, which mediates its strong nuclear accumulation. These data suggest that active transport between the nucleus and cytoplasm may constitute an important regulatory mechanism for Survivin function. (C) 2002 Elsevier Science (USA).