文章：

RHO-GTPases和癌症

RHO–GTPases and cancer

原文发布日期：2002-02-01

DOI: 10.1038/nrc725

类型: Review Article

开放获取: 否

要点：

1. The RHO genes encode a related family of proteins that can bind to and hydrolyse GTP. When bound to GTP, they can bind to effector proteins and modulate cell behaviour and cell morphology.
2. Activated RHO-protein mutants are capable of transforming fibroblasts, and dominant inhibitory mutants of RHO proteins block transformation by RAS. There is increasing evidence that RHO proteins are deregulated during tumour progression and that this correlates with poor prognosis.
3. Modulation of RHO-protein activity can promote the metastasis of tumour cells by disrupting epithelial-sheet organization, increasing cell motility and promoting the degradation of the extracellular matrix.
4. RHO proteins can promote cell-cycle progression, which is controlled by cyclin-dependent kinases (CDKs). RHO proteins affect CDK activity by regulating the levels of cyclin D1, as well as p21^WAF1 and p27^KIP1, which bind to and modulate CDK activity. There is also evidence that RHO proteins might protect cells against apoptosis.
5. Given the involvement of RHO proteins in cancer, they might make good therapeutic targets. Methods of interfering with RHO function include: inhibition of membrane localization; blocking the function of RHO–GEFs (guanine nucleotide exchange factors); preventing RHO's interaction with its effectors; and inhibiting RHO's effector functions.

要点翻译：

1. RHO基因编码一个相关的蛋白质家族，这些蛋白质能够结合并水解GTP。当与GTP结合时，它们可与效应蛋白结合并调节细胞行为与细胞形态。
2. 激活的RHO蛋白突变体能够转化成纤维细胞，而RHO蛋白的显性抑制突变体可阻断RAS介导的转化作用。越来越多证据表明，RHO蛋白在肿瘤进展过程中会出现失调，且这与不良预后相关。
3. RHO蛋白活性的调控可通过以下方式促进肿瘤细胞转移：破坏上皮片层结构、增强细胞运动性以及促进细胞外基质降解。
4. RHO蛋白能促进由细胞周期蛋白依赖性激酶（CDK）控制的细胞周期进程。它通过调节细胞周期蛋白D1、p21WAF1和p27KIP1的水平来影响CDK活性——这些蛋白能结合并调节CDK功能。另有证据表明RHO蛋白可能保护细胞免于凋亡。
5. 鉴于RHO蛋白在癌症中的参与度，它们可能成为良好的治疗靶点。干预RHO功能的方法包括：抑制膜定位；阻断RHO-GEFs（鸟嘌呤核苷酸交换因子）功能；阻止RHO与效应因子的相互作用；以及抑制RHO的效应器功能。

英文摘要：

The RAS oncogenes were identified almost 20 years ago. Since then, we have learnt that they are members of a large family of small GTPases that bind GTP and hydrolyse it to GDP. This is then exchanged for GTP and the cycle is repeated. The switching between these two states regulates a wide range of cellular processes. A branch of the RAS family — the RHO proteins — is also involved in cancer, but what is the role of these proteins and would they make good therapeutic targets?

摘要翻译： 

RAS癌基因早在近20年前就被发现了。此后我们了解到，它们属于一个庞大的小GTP酶家族，能结合GTP并将其水解为GDP，随后GDP又被GTP替换，循环往复。这两种状态之间的切换调控着多种细胞过程。RAS家族的一个分支——RHO蛋白——也与癌症相关，但这些蛋白究竟起什么作用？它们是否可作为良好的治疗靶点？

原文链接：

RHO–GTPases and cancer