The Ras-association domain family (RASSF) members and their role in human tumourigenesis.
The Ras-association domain family (RASSF) members and their role in human tumourigenesis.
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DOI：
10.1016/j.bbcan.2007.06.003
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发表时间：
2007-09
影响因子：
11.2
通讯作者：
Adams, David J.
中科院分区：
文献类型：
--
作者：
van der Weyden, Louise;Adams, David J.
Ras蛋白在人类癌症中发挥直接因果作用，大约30%的肿瘤中发生Ras激活突变。Ras效应物也有助于癌症，因为Ras效应物中发生突变，特别是B-Raf和PI 3-K，并且阻断这些途径的药物正在临床开发中。在2000年，一种新的Ras效应子被鉴定，RAS相关结构域家族1（RASSF 1），该基因的RASSF 1A亚型的表达在肿瘤中通过其启动子的甲基化而沉默。由于甲基化是可逆的，去甲基化剂目前正在临床试验中使用，因此通过启动子超甲基化检测RASSF 1A沉默在癌症诊断、预后和治疗中具有潜在的临床用途。RASSF 1A属于RAS效应子的新家族，目前有8个成员（RASSF 1 -8）。RASSF 1 -6各自含有可变的N-末端区段，随后是Ral-GDS/AF 6类型的Ras-缔合（RA）结构域，以及延伸至C-末端的称为SARAH结构域的专门卷曲螺旋结构。RASSF 7 -8含有一个N-末端RA结构域和一个可变的C-末端。RASSF家族的成员被认为是通过调节细胞周期和细胞凋亡来发挥肿瘤抑制剂的作用。本文将总结我们目前对RASSF家族每个成员的了解，特别是它们在肿瘤发生中发挥的作用，特别关注RASSF 1A，其启动子甲基化是人类肿瘤中最常见的改变之一。
Ras proteins play a direct causal role in human cancer with activating mutations in Ras occurring in ∼ 30% of tumours. Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development. In 2000, a new Ras effector was identified, RAS-association domain family 1 (RASSF1), and expression of the RASSF1A isoform of this gene is silenced in tumours by methylation of its promoter. Since methylation is reversible and demethylating agents are currently being used in clinical trials, detection of RASSF1A silencing by promoter hypermethylation has potential clinical uses in cancer diagnosis, prognosis and treatment. RASSF1A belongs to a new family of RAS effectors, of which there are currently 8 members (RASSF1–8). RASSF1–6 each contain a variable N-terminal segment followed by a Ras-association (RA) domain of the Ral-GDS/AF6 type, and a specialised coiled-coil structure known as a SARAH domain extending to the C-terminus. RASSF7–8 contain an N-terminal RA domain and a variable C-terminus. Members of the RASSF family are thought to function as tumour suppressors by regulating the cell cycle and apoptosis. This review will summarise our current knowledge of each member of the RASSF family and in particular what role they play in tumourigenesis, with a special focus on RASSF1A, whose promoter methylation is one of the most frequent alterations found in human tumours.
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