Haferkamp Sebastian, Scurr Lyndee L, Becker Therese M, Frausto Monika, Kefford Richard F, Rizos Helen
Westmead Institute for Cancer Research, Westmead Hospital, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
J Invest Dermatol. 2009 Aug;129(8):1983-91. doi: 10.1038/jid.2009.5. Epub 2009 Feb 12.
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.
癌基因诱导的衰老被认为是细胞转化的强大障碍，并且在肿瘤发展的早期阶段已在体内观察到。人类痣细胞经常表达致癌性N-RAS或B-RAF，并且被认为处于永久生长停滞状态。许多研究表明，p16（INK4a）以及在较小程度上的p14ARF肿瘤抑制蛋白是痣中癌基因诱导衰老的关键触发因素，因此这些蛋白是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。在本研究中，我们研究了黑色素瘤相关的N-RAS（Q61K）对黑素细胞衰老的影响，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。我们正式表明，培养的人类黑素细胞可以在不存在INK4a/ARF编码蛋白的情况下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衰老的INK4a/ARF非依赖性分子途径。
