Destabilization of cyclin D1 message plays a critical role in cell cycle exit upon mitogen withdrawal
Destabilization of cyclin D1 message plays a critical role in cell cycle exit upon mitogen withdrawal
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DOI：
10.1038/sj.onc.1208299
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发表时间：
2005-02-03
期刊：
影响因子：
8
通讯作者：
Hitomi, M
中科院分区：
文献类型：
--
作者：
Guo, Y;Harwalkar, J;Hitomi, M
细胞周期蛋白 D1 对于细胞分裂周期的进入、持续和退出至关重要。静止细胞的有丝分裂原刺激以转录依赖性方式诱导细胞周期蛋白 D1 表达。另一方面，在活跃循环的细胞中，细胞周期中细胞周期蛋白 D1 蛋白水平的波动受到转录后调节。 Cyclin D1 在 S 期以低水平表达，以实现有效的 DNA 合成，并在 G2 期通过 Ras 活性诱导至高水平，以使细胞持续进行细胞周期进程。一旦在 G2 期被诱导，细胞周期蛋白 D1 的表达在下一个 G1 期变得不依赖于 Ras，从而促进 G1/S 转变。然而，当有丝分裂信号被消除时，细胞周期蛋白 D1 在 G2 期无法增加，并且细胞在下一个 G1 期停滞。这样，G2期cyclin D1的表达水平决定了下一个细胞周期的命运。尽管细胞周期蛋白 D1 抑制在有丝分裂原撤除后的机制很重要，但其机制尚不清楚。使用定量荧光显微镜和生化分析，我们发现，在血清剥夺后，细胞周期蛋白 D1 mRNA 下调，但其转录率没有任何下降。此外，当血清被去除时，细胞周期蛋白 D1 mRNA 的半衰期会变短。这些结果表明，细胞周期蛋白 D1 信息不稳定在去血清培养物 G2 期期间细胞周期蛋白 D1 抑制中发挥着关键作用，因此在细胞周期退出中发挥着关键作用。
Cyclin D1 is critical for entry into, continuation of, and exit from the cell division cycle. Mitogen stimulation of quiescent cells induces cyclin D1 expression in a transcription-dependent manner. In actively cycling cells, on the other hand, fluctuation of cyclin D1 protein levels through the cell cycle is post-transcriptionally regulated. Cyclin D1 is expressed at low levels during S phase to allow efficient DNA synthesis, and induced to high levels in G2 phase through Ras activity to commit the cells to continuing cell cycle progression. Once induced in G2 phase, cyclin D1 expression becomes Ras independent through the next G1 phase, where it promotes G1/S transition. When mitogenic signaling is abrogated, however, cyclin D1 fails to increase during G2 phase and the cell becomes arrested in the next G1 phase. In this way, the expression levels of cyclin D1 in G2 phase determine the fate of the next cell cycle. Despite its importance of the mechanism of cyclin D1 suppression upon mitogen withdrawal is unknown. Using both quantitative fluorescence microscopy and biochemical analyses, we have found that, upon serum deprivation, cyclin D1 mRNA is downmodulated without any decline in its rate of transcription. Furthermore, cyclin D1 mRNA half-life becomes shorter when serum is removed. These results demonstrate that cyclin D1 message destabilization plays a critical role in cyclin D1 suppression during G2 phase of serum-deprived cultures, and therefore in the withdrawal from the cell cycle.