Oncogene-Induced Senescence Does Not Require the p16INK4a or p14ARF Melanoma Tumor Suppressors
Oncogene-Induced Senescence Does Not Require the p16INK4a or p14ARF Melanoma Tumor Suppressors
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DOI：
10.1038/jid.2009.5
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发表时间：
2009-08-01
影响因子：
6.5
通讯作者：
Rizos, Helen
中科院分区：
文献类型：
--
作者：
Haferkamp, Sebastian;Scurr, Lyndee L.;Rizos, Helen
癌基因诱导的衰老被认为是细胞转化的有效屏障，并且在肿瘤发展的早期阶段就已在体内观察到。人类痣细胞经常表达致癌性 N-RAS 或 B-RAF，并且被认为会永久生长停滞。许多研究表明，p16(INK4a) 以及较小程度上的 p14ARF 肿瘤抑制蛋白是癌基因诱导的痣衰老的关键触发因素，因此这些蛋白代表了黑色素瘤进展的主要抑制剂。然而，也有报道表明 p16(INK4a) 和/或 p14ARF 不足以执行癌基因诱导的衰老程序。在这项研究中，我们检查了黑色素瘤相关的 N-RAS (Q61K) 对黑色素细胞衰老的影响，并利用 RNA 干扰载体直接评估人类 p14ARF 和 p16 (INK4a) 基因对 N-RAS 诱导的衰老程序的个体贡献。我们正式证明，在缺乏 INK4a/ARF 编码蛋白的情况下，培养的人类黑素细胞可以启动有效的癌基因介导的衰老程序。我们的数据与衰老痣细胞并不总是表达 p16(INK4a) 的观察结果一致，并强调需要彻底探索人类黑素细胞中不依赖于 INK4a/ARF 的衰老分子途径。
Oncogene-induced senescence is considered to act as a potent barrier to cell transformation, and has been seen in vivo during the early stages of tumor development. Human nevus cells frequently express oncogenic N-RAS or B-RAF, and are thought to be permanently growth arrested. Many studies have suggested that the p16(INK4a) and, to a lesser extent, the p14ARF tumor suppressor proteins act as critical triggers of oncogene-induced senescence in nevi, and thus these proteins represent major inhibitors of progression to melanoma. There have also been reports, however, showing that p16(INK4a) and/or p14ARF is not sufficient to execute the oncogene-induced senescence program. In this study, we examined the impact of melanoma-associated N-RAS(Q61K) on melanocyte senescence and utilized RNA-interference vectors to directly assess the individual contribution of human p14ARF and p16(INK4a) genes to the N-RAS-induced senescence program. We formally show that cultured human melanocytes can initiate an effective oncogene-mediated senescence program in the absence of INK4a/ARF-encoded proteins. Our data are consistent with observations showing that senescent nevus cells do not always express p16(INK4a), and highlight the need to thoroughly explore INK4a/ARF-independent molecular pathways of senescence in human melanocytes.