A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity
A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity
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DOI：
10.1016/j.cell.2005.04.017
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发表时间：
2005-06-17
期刊：
影响因子：
64.5
通讯作者：
Agami, R
中科院分区：
文献类型：
--
作者：
Kolfschoten, IGM;van Leeuwen, B;Agami, R
RAS的激活突变经常发生在人类癌症的亚群中，这表明RAS的激活对肿瘤发生很重要。然而，这些癌症的很大一部分仍然保留了野生型RAS等位基因，这表明RAS途径要么以一种独特的方式被激活，要么另一种途径被解除调控。为了发现新的肿瘤抑制基因，我们筛选了一个rna干扰文库，用于在缺乏外源性致癌RAS的情况下转化人原代细胞的敲除构建物。在这里，我们报道了PITX1的鉴定，其抑制诱导RAS通路和致瘤性。有趣的是，我们观察到PITX1在前列腺和膀胱肿瘤以及含有野生型RAS的结肠癌细胞系中的低表达。结肠癌细胞中PITX1的恢复以野生型ras依赖的方式抑制肿瘤的发生。最后，我们发现RAS- gtpase激活蛋白RASAL1是PITX1影响RAS功能的转录靶点。因此，PITX1通过RASAL1下调RAS通路抑制致瘤性。
Activating mutations of RAS frequently occur in subsets of human cancers, indicating that RAS activation is important for tumorigenesis. However, a large proportion of these cancers still retain wild-type RAS alleles, suggesting that either the RAS pathway is activated in a distinct manner or another pathway is deregulated. To uncover novel tumor-suppressor genes, we screened an RNA-interference library for knockdown constructs that transform human primary cells in the absence of ectopically introduced oncogenic RAS. Here we report the identification of PITX1, whose inhibition induces the RAS pathway and tumorigenicity. Interestingly, we observed low expression of PITX1 in prostate and bladder tumors and in colon cancer cell lines containing wild-type RAS. Restoration of PITX1 in the colon cancer cells inhibited tumorigenicity in a wild-type RAS-dependent manner. Finally, we identified RASAL1, a RAS-GTPase-activating protein, as a transcription target through which PITX1 affects RAS function. Thus, PITX1 suppresses tumorigenicity by downregulating the RAS pathway through RASAL1.