Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation
Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation
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DOI：
10.1101/gad.854900
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发表时间：
2000-12-15
影响因子：
10.5
通讯作者：
Diehl, JA
中科院分区：
文献类型：
--
作者：
Alt, JR;Cleveland, JL;Diehl, JA
GSK-3 β依赖性的细胞周期蛋白D1在Thr-286的磷酸化促进细胞周期S期细胞周期蛋白D1从核到胞质的再分布，但磷酸化如何调节再分布尚未解决。例如，核细胞周期蛋白D1的磷酸化可以增加其核输出相对于核输入的速率;或者，GSK-3 β磷酸化细胞质细胞周期蛋白D1可以抑制核输入。在这里，我们报道GSK-3 β依赖性磷酸化通过促进细胞周期蛋白D1与细胞核输出蛋白CRM 1的结合促进细胞周期蛋白D1的细胞核输出。D1-T286 A是一种不能被GSK-3 β磷酸化的细胞周期蛋白D1突变体，在整个细胞周期中保持在细胞核内，这是其与CRM 1结合减少的结果。鼠成纤维细胞中细胞周期蛋白D1-T286 A的组成性过表达导致细胞转化并促进免疫受损小鼠中的肿瘤生长。因此，在S期细胞周期蛋白D1从细胞核中去除似乎是调节细胞分裂所必需的。
GSK-3 beta -dependent phosphorylation of cyclin D1 at Thr-286 promotes the nuclear-to-cytoplasmic redistribution of cyclin D1 during S phase of the cell cycle, but how phosphorylation regulates redistribution has not been resolved. For example, phosphorylation of nuclear cyclin D1 could increase its rate of nuclear export relative to nuclear import; alternatively, phosphorylation of cytoplasmic cyclin D1 by GSK-3 beta could inhibit nuclear import. Here, we report that GSK-3 beta -dependent phosphorylation promotes cyclin D1 nuclear export by facilitating the association of cyclin D1 with the nuclear exportin CRM1. D1-T286A, a cyclin D1 mutant that cannot be phosphorylated by GSK-3 beta, remains nuclear throughout the cell cycle, a consequence of its reduced binding to CRM1. Constitutive overexpression of the nuclear cyclin D1-T286A in murine fibroblasts results in cellular transformation and promotes tumor growth in immune compromised mice. Thus, removal of cyclin D1 from the nucleus during S phase appears essential for regulated cell division.