Alessandrini A, Chiaur D S, Pagano M
Renal Unit, Massachusetts General Hospital East, USA.
Leukemia. 1997 Mar;11(3):342-5. doi: 10.1038/sj.leu.2400581.
The cell cycle has been the object of extensive studies for the past years. A complex network of molecular interactions has been identified. In particular, a class of cell cycle inhibitory proteins has been cloned and characterized but details of the molecular mechanism of their action have yet to be resolved. These inhibitors regulate the progression through G1 and the G1/S transition via the inhibition of the cyclin-dependent kinase (Cdk) activity. The potential function of these negative regulators as tumor suppressors provides new insights into the link between the cell cycle and oncogenesis. p27 is a potent inhibitor of Cdks. In quiescent cells p27 accumulates without an increase in mRNA or protein synthesis. Cell cycle regulation of p27 levels, both in normal and transformed human cells, occurs via the ubiquitin-proteasome pathway and, compared to proliferating cells, quiescent cells contain a far lower amount of p27 ubiquitinating activity. The specific proteolysis of p27 is probably involved in the pathway of activation of Cdks. p27 is a phosphoprotein and its phosphorylation is cell cycle regulated. Often phosphorylation is a signal for ubiquitination. p27 is phosphorylated exclusively on serine by Erk1 and almost exclusively on threonine by Cdk1 in in vitro experiments. This finding raises the question of whether and how phosphorylation by these kinases is involved in the process of p27 proteolysis.
在过去的几年里，细胞周期一直是广泛研究的对象。人们已经确定了一个复杂的分子相互作用网络。特别是，一类细胞周期抑制蛋白已被克隆和表征，但其作用的分子机制细节尚未得到解决。这些抑制剂通过抑制细胞周期蛋白依赖性激酶（Cdk）的活性来调节G1期进程和G1/S转换。这些负调控因子作为肿瘤抑制因子的潜在功能为细胞周期与肿瘤发生之间的联系提供了新的见解。p27是一种有效的Cdk抑制剂。在静止细胞中，p27积累，而mRNA或蛋白质合成没有增加。在正常和转化的人类细胞中，p27水平的细胞周期调节是通过泛素-蛋白酶体途径进行的，与增殖细胞相比，静止细胞中p27泛素化活性要低得多。p27的特异性蛋白水解可能参与了Cdk的激活途径。p27是一种磷蛋白，其磷酸化受细胞周期调节。通常磷酸化是泛素化的信号。在体外实验中，Erk1仅在丝氨酸上磷酸化p27，而Cdk1几乎仅在苏氨酸上磷酸化p27。这一发现提出了这些激酶的磷酸化是否以及如何参与p27蛋白水解过程的问题。
