Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology*
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Genes, ras*
  • Humans
  • Melanocytes / cytology*
  • Melanoma / pathology
  • Melanoma / prevention & control*
  • Proto-Oncogene Proteins c-akt / physiology
  • Tumor Suppressor Protein p14ARF / physiology*
  • Tumor Suppressor Proteins / physiology*


  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases