Glycogen synthase kinase 3β regulates cyclin D1 proteolysis and subcellular localization
Glycogen synthase kinase 3β regulates cyclin D1 proteolysis and subcellular localization
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DOI：
10.1101/gad.12.22.3499
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发表时间：
1998-11-15
影响因子：
10.5
通讯作者：
Sherr, CJ
中科院分区：
文献类型：
--
作者：
Diehl, JA;Cheng, MG;Sherr, CJ
细胞周期蛋白D依赖性激酶的活性在G（1）期期间将细胞外信号传导与调节DNA复制和有丝分裂的fell循环引擎整合。诱导D型细胞周期蛋白和它们组装成全酶复合物依赖于促分裂原刺激。相反，D型细胞周期蛋白是不稳定的蛋白质，这一事实保证了当细胞缺乏有丝分裂原时，亚基库迅速缩小。磷酸化的细胞周期蛋白D1的一个单一的苏氨酸残基附近的羧基末端（Thr-286）正调节D1的蛋白酶体降解。现在，我们证明糖原合成酶激酶-3 β（GSK-3 β）磷酸化细胞周期蛋白D1特异性的Thr-286，从而触发快速细胞周期蛋白D1的营业额。因为GSK-3 β的活性可以通过依次涉及Ras、磷脂酰肌醇-3-OH激酶（PI 3 K）和蛋白激酶B（Akt）的途径的信号传导而被抑制，所以细胞周期蛋白D1的周转与其组装一样也是Ras依赖性的，因此是受有丝分裂原调节的。相比之下，在PI 3 K信号传导中有缺陷的Ras突变体，或在Ras下游起作用以激活细胞外信号调节蛋白激酶（ERK）的组成型活性促分裂原活化蛋白激酶-激酶（MEK 1）突变体，不能稳定细胞周期蛋白D1。与细胞周期蛋白D1（其在G（1）期期间在细胞核中积累并在S期期间退出到细胞质中）直接相反，GSK-3 β在G（1）期期间主要在细胞质中，但在S期期间显著部分进入细胞核。一种高度稳定的D1突变体，其中丙氨酸取代了位置286处的苏氨酸，并且在整个细胞周期中保留在细胞核中，该突变体对GSK-3 β的磷酸化反应不敏感。在小鼠成纤维细胞中，GSK-3 β的活性（而非激酶缺陷）形式的过表达导致细胞周期蛋白D1从细胞核重新分布到细胞质。因此，细胞周期蛋白D1的磷酸化和蛋白水解周转及其在细胞分裂周期中的亚细胞定位通过GSK-3 β的作用相关联。
The activities of cyclin D-dependent kinases serve to integrate extracellular signaling during G(1) phase with the fell-cycle engine that regulates DNA replication and mitosis. Induction of D-type cyclins and their assembly into holoenzyme complexes depend on mitogen stimulation. Conversely, the fact that D-type cyclins are labile proteins guarantees that the subunit pool shrinks rapidly when cells are deprived of mitogens. Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1. Now, we demonstrate that glycogen synthase kinase-3 beta (GSK-3 beta) phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover. Because the activity of GSK-3 beta can be inhibited by signaling through a pathway that sequentially involves Ras, phosphatidylinositol-3-OH kinase (PI3K), and protein kinase B (Akt), the turnover of cyclin D1, like its assembly, is also Ras dependent and, hence, mitogen regulated. In contrast, Ras mutants defective in PI3K signaling, or constitutively active mitogen-activated protein kinase-kinase (MEK1) mutants that act downstream of Ras to activate extracellular signal-regulated protein kinases (ERKs), cannot stabilize cyclin D1. In direct contrast to cyclin D1, which accumulates in the nucleus during G(1) phase and exits into the cytoplasm during S phase, GSK-3 beta is predominantly cytoplasmic during G(1) phase, but a significant fraction enters the nucleus during S phase. A highly stable D1 mutant in which an alanine is substituted for the threonine at position 286 and that is refractory to phosphorylation by GSK-3 beta remained in the nucleus throughout the cell cycle. Overexpression of an active, but not a kinase-defective, form of GSK-3 beta in mouse fibroblasts caused a redistribution of cyclin D1 from the cell nucleus to the cytoplasm. Therefore, phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK-3 beta.