文章：

Ral GTP酶与癌症：致瘤平台的关键支持

Ral GTPases and cancer: linchpin support of the tumorigenic platform

原文发布日期：2008-02-01

DOI: 10.1038/nrc2296

类型: Review Article

开放获取: 否

要点：

1. Chronic activation of the Ras-like (Ral) guanyl nucleotide-binding proteins, RALA and RALB, occurs in tumour-derived cell lines and tumour samples.
2. Depletion of RALA severely impairs the anchorage-independent proliferation of cancer cell lines, whereas RALB seems to be essential for the survival of a variety of tumour-derived cell lines.
3. RALA is phosphorylated by Aurora kinase A and other, yet to be identified kinases. It is also a substrate of protein phosphatase 2A Aβ. Evidence indicates that dephosphorylation of RALA is a major mechanism by which PP2A Aβ normally restricts tumour progression.
4. The effects on tumorigenesis of well-characterised downstream effectors of Ral, such as the Rac-family GTPase-activating protein RLIP, the Y-box transcription factor ZO-1-associated nucleic acid-binding protein (ZONAB) and two subunits of the exocyst complex, SEC5 and EXO84, remain unclear. However, a number of relationships have been identified that might explain Ral-dependent modulation of cell proliferation and survival.
5. An important factor that might explain the occurrence of Ral activation in tumorigenesis is the RALB-specific contribution to cancer cell survival through activation of TANK-binding kinase 1 (TBK1). Chronic RALB activation restricts initiation of apoptotic programmes that are normally activated in the context of oncogenic stress.
6. Proteins such as TBK1 might prove to be good candidate targets for the development of cancer drugs with a large therapeutic window.

要点翻译：

1. Ras样（Ral）鸟苷结合蛋白RALA和RALB的慢性激活现象常见于肿瘤来源的细胞系及肿瘤样本。
2. 敲低RALA会严重损害癌细胞系的锚定非依赖性增殖能力，而RALB似乎对多种肿瘤来源细胞系的存活至关重要。  
3. RALA可被极光激酶A及其他尚未明确的激酶磷酸化，同时也是蛋白磷酸酶2A Aβ的底物。有证据表明，RALA的去磷酸化是PP2A Aβ抑制肿瘤进展的主要机制。  
4. 目前对Ral明确下游效应因子（如Rac家族GTP酶激活蛋白RLIP、Y-box转录因子ZO-1相关核酸结合蛋白ZONAB，以及外泌体复合物的两个亚基SEC5和EXO84）在肿瘤发生中的作用尚不明确。但已发现的一系列关联或许能解释Ral对细胞增殖与存活的调控机制。  
5. RALB通过激活TANK结合激酶1（TBK1）促进癌细胞存活，这一特异性作用可能是解释Ral在肿瘤发生中被激活的关键因素。持续的RALB激活会抑制通常因致癌应激而启动的凋亡程序。  
6. 像TBK1这类蛋白有望成为开发具有宽治疗窗抗癌药物的理想靶点候选。

英文摘要：

A confluence of recent observations has indicted the Ras-family G-proteins RALA and RALB as key offenders in the subversion of core biological systems driving oncogenic transformation. Here, we will focus on current developments highlighting the pivotal contribution of Ral proteins to the regulatory framework supporting tumorigenesis, and evaluate mechanistic connections between Ral effector activation and generation of this framework.

摘要翻译： 

近期多项研究共同表明，Ras家族G蛋白RALA和RALB是破坏驱动肿瘤转化的核心生物系统的“元凶”。本文将聚焦于最新进展，强调Ral蛋白在支撑肿瘤发生的调控框架中的关键作用，并评估Ral效应子激活与该框架形成之间的机制联系。

原文链接：

Ral GTPases and cancer: linchpin support of the tumorigenic platform