文章目录

周期还是非周期：癌症治疗的关键决定

To cycle or not to cycle: a critical decision in cancer

原文发布日期：2001-12-01

DOI: 10.1038/35106065

类型: Review Article

开放获取: 否

要点：

要点翻译：

英文摘要：

摘要翻译：

原文链接：

文章：

周期还是非周期：癌症治疗的关键决定

To cycle or not to cycle: a critical decision in cancer

原文发布日期：2001-12-01

DOI: 10.1038/35106065

类型: Review Article

开放获取: 否

要点：

The cell cycle is regulated by cyclin-dependent kinases (CDKs), which form active heterodimeric kinases when bound to the cyclins. Active CDK–cyclin complexes can be negatively regulated by two families of inhibitors, the INK4 and the WAF1/KIP proteins.
The CDK4/6–cyclin-D and CDK2–cyclin-E complexes are active in G1, and CDK2–cyclin-A and CDK1–cyclin-A are active in S phase. The CDK complex responsible for driving cells through mitosis is CDK1–cyclin B.
The main G1 substrates of CDKs are the retinoblastoma family (RB, p107 and p130). RB is sequentially phosphorylated by CDK4/6–cyclin-D and CDK2–cyclin-E complexes. This phosphorylation inactivates the growth-suppression properties of RB and stimulates progression through G1 and into S phase.
The basic regulators of G1 progression are altered in most human cancers. Genetic alterations usually affect CDK4 and CDK6, their positive (mainly cyclin D1) and negative (INK4A and INK4B) regulators and their substrates (mainly RB).
Deregulation of CDK2 activity frequently results from the alteration in the expression levels of its regulators cyclin E and KIP1. The cause of these alterations is not clear. Recently, some members of the proteolysis pathways involved in the control of cyclin E and KIP1 protein levels have been found to be altered in certain types of cancer.
A few other cell-cycle regulators, mostly those involved in the mitotic spindle checkpoint, are also deregulated in human cancer. They include BUB proteins, MAD2, the Aurora kinases, PLK1 and securin. The evidence for their involvement in human cancer is, so far, scarce.
The generation of gene-targeted mice has illustrated the importance of G1 regulators in tumour development. Although most of these are not essential for cell-cycle progression or mouse development, their deregulation often leads to tumour development.
The understanding of G1 regulation has opened new avenues to search for antitumor drugs. Although there are several ways to control CDK activity, small-molecule CDK inhibitors are the preferred tools, at this time. So far, several CDK inhibitors (mainly CDK2 and pan-CDK inhibitors) are in advanced preclinical studies and at least two of them — flavopiridol and UCN-01 — have reached clinical trials.

要点翻译：

细胞周期受细胞周期蛋白依赖性激酶（CDK）的调控，当CDK与细胞周期蛋白结合时会形成具有活性的异源二聚体激酶。活化的CDK-细胞周期蛋白复合物可受到INK4和WAF1/KIP蛋白两类抑制因子的负向调控。
CDK4/6-细胞周期蛋白D和CDK2-细胞周期蛋白E复合物在G1期具有活性，而CDK2-细胞周期蛋白A和CDK1-细胞周期蛋白A在S期具有活性。负责驱动细胞通过有丝分裂的是CDK1-细胞周期蛋白B复合物。
CDK在G1期的主要底物是视网膜母细胞瘤蛋白家族（RB、p107和p130）。RB会依次被CDK4/6-细胞周期蛋白D和CDK2-细胞周期蛋白E复合物磷酸化。这种磷酸化作用会抑制RB的生长抑制特性，并刺激细胞通过G1期进入S期。
在大多数人类癌症中，G1期进程的基础调控因子会发生改变。基因改变通常影响CDK4和CDK6、它们的正向调控因子（主要是细胞周期蛋白D1）和负向调控因子（INK4A和INK4B）以及它们的底物（主要是RB）。
CDK2活性的失调通常源于其调控因子细胞周期蛋白E和KIP1表达水平的改变，这些改变的具体原因尚不明确。近期研究发现，在某些特定类型的癌症中，参与调控细胞周期蛋白E和KIP1蛋白水平的蛋白酶解通路部分成员发生了改变。
其他一些细胞周期调控因子（主要涉及纺锤体组装检查点）在人类癌症中也存在失调现象，包括BUB蛋白、MAD2、极光激酶、PLK1和分离抑制蛋白等。但目前关于这些因子参与人类癌症的证据尚不充分。
基因靶向小鼠模型的研究揭示了G1期调控因子在肿瘤发展中的重要性。尽管这些因子大多数并非细胞周期进程或小鼠发育所必需，但其功能失调往往会导致肿瘤发生。
对G1期调控机制的理解为寻找抗肿瘤药物开辟了新途径。虽然存在多种调控CDK活性的方法，但目前小分子CDK抑制剂是首选工具。迄今已有数种CDK抑制剂（主要是CDK2抑制剂和泛CDK抑制剂）进入 advanced 临床前研究阶段，其中至少两种——夫拉平度（flavopiridol）和UCN-01——已进入临床试验阶段。

英文摘要：

Tumour cells undergo uncontrolled proliferation, yet tumours most often originate from adult tissues, in which most cells are quiescent. So, the proliferative advantage of tumour cells arises from their ability to bypass quiescence. This can be due to increased mitogenic signalling and/or alterations that lower the threshold required for cell-cycle commitment. Understanding the molecular mechanisms that underlie this commitment should provide important insights into how normal cells become tumorigenic and how new anticancer strategies can be devised.