期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 129, 期 8, 页码 1983-1991出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2009.5
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资金
- National Health and Medical Research Council of Australia (NHMRC) [402761]
- Health Department of NSW
- Australian Cancer Research Foundation
- Cancer Institute of NSW
- Cameron Melanoma Research, Melanoma and Skin Cancer Research Institute, University of Sydney
- German Academic Exchange Service (DAAD).
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.
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