Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities
Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities
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DOI：
10.1038/sj.onc.1206015
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发表时间：
2002-11-28
期刊：
影响因子：
8
通讯作者：
Dalton, S
中科院分区：
文献类型：
--
作者：
Stead, E;White, J;Dalton, S
胚胎来源的多能细胞以异常快的速度增殖，并具有具有截短间隙期的特征性细胞周期结构。为了定义其分子基础，我们描述了小鼠胚胎干细胞和早期原始外胚层样细胞的细胞周期控制。这些细胞表现出早熟的 Cdk2、细胞周期蛋白 A 和细胞周期蛋白 E 激酶活性，这些活性明显与细胞周期无关。抑制 Cdk2 活性可显着减少多能细胞的循环时间，表明它是快速细胞分裂的限速因素，尽管这对细胞周期结构和延长间隙期的建立没有影响。 Cdc2-cyclin B 是唯一被确定在多能细胞中受细胞周期调节的 Cdk 活性。细胞周期蛋白 B 水平的细胞周期调节和 Cdc2 的 Y-15 调节有助于 Cdc2-细胞周期蛋白 B 活性的时间变化。 E2F 靶基因在整个细胞周期中持续活跃，反映了 p107 和 pRb 等口袋蛋白的低活性以及 pRb 激酶的持续活性。这些结果表明，胚胎起源的原始细胞中的快速细胞分裂周期是由缺乏正常细胞周期周期性的极端水平的 Cdk 活性驱动的。
Pluripotent cells of embryonic origin proliferate at unusually rapid rates and have a characteristic cell cycle structure with truncated gap phases. To define the molecular basis for this we have characterized the cell cycle control of murine embryonic stem cells and early primitive ectoderm-like cells. These cells display precocious Cdk2, cyclin A and cyclin E kinase activities that are conspicuously cell cycle independent. Suppression of Cdk2 activity significantly decreased cycling times of pluripotent cells, indicating it to be rate-limiting for rapid cell division, although this had no impact on cell cycle structure and the establishment of extended gap phases. Cdc2-cyclin B was the only Cdk activity that was identified to be cell cycle regulated in pluripotent cells. Cell cycle regulation of cyclin B levels and Y-15 regulation of Cdc2 contribute to the temporal changes in Cdc2-cyclin B activity. E2F target genes are constitutively active throughout the cell cycle, reflecting the low activity of pocket proteins such as p107 and pRb and constitutive activity of pRb-kinases. These results show that rapid cell division cycles in primitive cells of embryonic origin are driven by extreme levels of Cdk activity that lack normal cell cycle periodicity.