文章：

细胞骨架的调控：cdk抑制剂的致癌功能？

Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?

原文发布日期：2004-12-01

DOI: 10.1038/nrc1501

类型: Review Article

开放获取: 否

要点：

1. Recent evidence points to cell-cycle independent functions for cyclin, cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs). In particular, the involvement of these proteins in the regulation of the cytoskeleton and cell migration is emerging.
2. In subsets of many human tumour types, the function of CKIs of the Cip/Kip family is altered by relocation to the cytoplasm, rather than through mutation like most other tumour suppressors. The cytoplasmic localization of p21 (CIP1) and p27 (KIP1) is associated with high tumour grade, tumour cell invasiveness and metastasis.
3. Whereas the function of CKIs as tumour suppressors is well characterized in the nucleus, they also seem to function in the cytoplasm, where they regulate cytoskeletal functions. This occurs through the modulation of the Rho signalling pathway. This cytoplasmic function could be oncogenic, as inhibition of the Rho pathway can result in increased migratory capacity.
4. p27 binds to RhoA and prevents the interaction of RhoA with its activators the guanine-nucleotide exchange factors. Fibroblasts lacking p27 have impaired migration. CIP1 binds to and inhibits Rho kinases (ROCK1 and -2) — downstream effectors of Rho. p57 (KIP2) binds to and targets LIM domain-containing protein kinase (LIMK) to the nucleus, sequestering it in a compartment where it cannot regulate the actin cytoskeleton.
5. Rho GTPases regulate the levels and timing of expression of cell-cycle regulators, and cell-cycle regulators also regulate Rho signalling.
6. The regulation of the cytoskeleton and cell migration by CKIs might contribute to the process of tumorigenesis. Targeting these functions of CKIs might therefore constitute a new therapeutic strategy.

要点翻译：

1. 最新证据表明，细胞周期蛋白、细胞周期蛋白依赖性激酶（CDKs）及其抑制因子（CKIs）具有独立于细胞周期的功能。特别是这些蛋白质在细胞骨架调控和细胞迁移中的作用正逐渐被揭示。
2. 在多种人类肿瘤亚型中，Cip/Kip家族CKIs的功能改变更多源于其胞质移位，而非像其他抑癌基因那样通过突变实现。p21（CIP1）和p27（KIP1）的胞质定位与肿瘤高级别、肿瘤细胞侵袭性和转移性密切相关。
3. 虽然CKIs在细胞核内作为抑癌因子的功能已明确，但它们似乎也在细胞质中通过调节Rho信号通路来调控细胞骨架功能。这种胞质功能可能具有致癌性，因为抑制Rho通路会增强细胞迁移能力。
4. p27通过结合RhoA并阻断其与鸟嘌呤核苷酸交换因子的相互作用来发挥作用。缺乏p27的成纤维细胞会出现迁移功能受损。CIP1可结合并抑制Rho下游效应物Rho激酶（ROCK1和-2）。p57（KIP2）则通过结合含LIM结构域的蛋白激酶（LIMK）并将其靶向至细胞核，使其无法调控肌动蛋白细胞骨架。
5. Rho GTP酶能调控细胞周期调节因子的表达水平和时序，而细胞周期调节因子同样可调控Rho信号传导。
6. CKIs对细胞骨架和细胞迁移的调控可能参与肿瘤发生过程。因此靶向CKIs的这些功能可能构成新的治疗策略。

英文摘要：

Cyclin-dependent kinase inhibitors (CKIs) are well known inhibitors of cell proliferation. Their activity is disrupted in many tumour types. Recent studies show that some of these proteins have interesting alternative functions, acting in the cytoplasm to regulate Rho signalling and thereby controlling cytoskeletal organization and cell migration. The upregulation of CKIs in the cytoplasm of many cancer cells indicates that although loss of nuclear CKIs is important for cancer cell proliferation, gain of cytoplasmic CKI function might be involved in tumour invasion and metastasis.

摘要翻译： 

细胞周期蛋白依赖性激酶抑制剂（CKIs）是众所周知的细胞增殖抑制因子。在多种肿瘤中，其活性常被破坏。最新研究表明，这些蛋白在胞质中具有新的功能：通过调控Rho信号通路影响细胞骨架重构和细胞迁移。许多癌细胞胞质中CKIs的上调提示，尽管核内CKIs缺失促进癌细胞增殖，但胞质CKIs功能获得可能参与肿瘤侵袭与转移过程。

原文链接：

Regulation of the cytoskeleton: an oncogenic function for cdk inhibitors?