Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors.
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.
Haferkamp
Sebastian
S
Westmead Institute for Cancer Research, Westmead Hospital, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
Scurr
Lyndee L
LL
Becker
Therese M
TM
Frausto
Monika
M
Kefford
Richard F
RF
Rizos
Helen
H
D045744:Cell Line, Tumor; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D008544:Melanocytes / Q000166:cytology*; D008545:Melanoma / Q000473:pathology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases