Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27
Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27
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DOI：
10.1093/emboj/18.19.5321
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发表时间：
1999-10-01
期刊：
影响因子：
11.4
通讯作者：
Eilers, M
中科院分区：
文献类型：
--
作者：
Bouchard, C;Thieke, K;Eilers, M
Myc的异位表达诱导静止细胞中Cdk 2激酶活性并拮抗p27（kip 1）与Cdk 2的结合。Myc介导这种作用的靶基因在很大程度上是未知的。我们现在表明，p27是快速和短暂的隔离由细胞周期蛋白D2-Cdk 4复合物激活的Myc和细胞周期蛋白D2是一个直接的靶基因的Myc。细胞周期蛋白D2启动子被Mad-Max复合物抑制，并通过一个高度保守的E-box元件被Myc去抑制。添加到静止细胞的抑制素A模拟激活Myc和诱导细胞周期蛋白D2的表达，表明细胞周期蛋白D2在静止细胞中以组蛋白脱乙酰酶依赖的方式被抑制。在已建立的细胞系中，通过异位表达p16或通过抗体注射抑制细胞周期蛋白D2的功能，抑制了Cdk 2和Myc诱导的细胞周期进入的P27的Myc依赖性解离。细胞周期蛋白D2缺陷的原代小鼠成纤维细胞在培养中加速衰老，并且不会被Myc永生化; Myc诱导的凋亡在这些细胞中不受损害。我们的数据确定了一个下游效应途径，直接连接Myc细胞周期的进展。
Ectopic expression of Myc induces Cdk2 kinase activity in quiescent cells and antagonizes association of p27(kip1) with Cdk2, The target gene(s) by which Myc mediates this effect is largely unknown. We now show that p27 is rapidly and transiently sequestered by cyclin D2-Cdk4 complexes upon activation of Myc and that cyclin D2 is a direct target gene of Myc. The cyclin D2 promoter is repressed by Mad-Max complexes and derepressed by Myc via a single highly conserved E-box element. Addition of trichostatin A to quiescent cells mimics activation of Myc and induces cyclin D2 expression, suggesting that cyclin D2 is repressed in a histone deacetylase-dependent manner in quiescent cells. Inhibition of cyclin D2 function in established cell lines, either by; ectopic expression of p16 or by antibody injection, inhibits Myc-dependent dissociation of p27 from Cdk2 and Myc-induced cell cycle entry. Primary mouse fibroblasts that are cyclin D2-deficient undergo accelerated senescence in culture and are not immortalized by Myc; induction of apoptosis by Myc is unimpaired in such cells. Our data identify a downstream effector pathway that links Myc directly to cell cycle progression.