Identification of a candidate tumor-suppressor gene specifically activated during Ras-induced senescence
Identification of a candidate tumor-suppressor gene specifically activated during Ras-induced senescence
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DOI：
10.1006/excr.2001.5434
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发表时间：
2002-02-15
影响因子：
3.7
通讯作者：
Serrano, M
中科院分区：
文献类型：
--
作者：
Barradas, M;Gonos, ES;Serrano, M
正常细胞对癌基因表现出保护性反应。值得注意的是，致癌Ras触发不可逆的增殖停滞，这让人想起复制衰老，并被认为是一种相关的肿瘤抑制机制。在这里，我们已经使用微阵列过滤器，以确定基因特异性上调Ras衰老的人成纤维细胞。在从微阵列中选择的最初一组基因中，我们发现了细胞周期抑制剂p21（Cip 1/Wnf 1），从而验证了筛选鉴定Ras衰老标记物和介质的效力。进一步详细分析了由Ras衰老期间更高度上调的那些基因形成的一组六个基因，以评估其特异性。特别是，我们研究了它们在细胞中的表达过度表达Ras，但抵抗Ras衰老的病毒癌蛋白E1 a;此外，我们还研究了它们在复制性衰老，有机体衰老，H2 O2诱导的衰老和DNA损伤过程中的表达。以这种方式，我们已经确定了一个新的基因，RIS 1（Ras诱导衰老1），这是不上调与任何上述过程，但专门在Ras衰老。此外，RIS 1也被转录因子Ets 2上调，Ets 2是Ras诱导衰老的已知介质。有趣的是，RIS 1位于染色体位置3p21.3，更具体地说，它被包括在一个只有1 Mb的短片段中，这是其他研究人员先前根据其肿瘤抑制活性定义的。总之，我们报告了一个新的基因，RIS 1，作为一个高度特异性的Ras诱导衰老的标志物和一个候选的肿瘤抑制基因的鉴定。(C)2002 Elsevier Science（美国）。
Normal cells display protective responses against oncogenes. Notably, oncogenic Ras triggers an irreversible proliferation arrest that is reminiscent of replicative senescence and that is considered a relevant tumor-suppressor mechanism. Here, we have used microarrayed filters to identify genes specifically upregulated in Ras-senescent human fibroblasts. Among the initial set of genes selected from the microarrays, we found the cell-cycle inhibitor p21(Cip1/Wnf1), thus validating the potency of the screening to identify markers and mediators of Ras-senescence. A group of six genes, formed by those more highly upregulated during Ras-senescence, was analyzed in further detail to evaluate their specificity. In particular, we examined their expression in cells overexpressing Ras but rendered resistant to Ras-senescence by the viral oncoprotein E1a; also, we have studied their expression during replicative senescence, organismal aging, H2O2-induced senescence, and DNA damage. In this manner, we have identified a novel gene, RIS1 (for Ras-induced senescence 1), which is not upregulated in association to any of the above-mentioned processes, but exclusively during Ras-senescence. Furthermore, RIS1 is also upregulated by the transcriptional factor Ets2, which is a known mediator of Ras-induced senescence. Interestingly, RIS1 is located at chromosomal position 3p21.3 and, more specifically, it is included in a short segment of just 1 Mb previously defined by other investigators for its tumor-suppressor activity. In summary, we report the identification of a novel gene, RIS1, as a highly specific marker of Ras-induced senescence and a candidate tumor-suppressor gene. (C) 2002 Elsevier Science (USA).