The p16 INK4A tumor suppressor regulates cellular oxidative stress

N. C. Jenkins, T. Liu, P. Cassidy, S. A. Leachman, K. M. Boucher, A. G. Goodson, G. Samadashwily, D. Grossman

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Mutations or deletions in the cyclin-dependent kinase inhibitor p16 INK4A are associated with multiple cancer types, but are more commonly found in melanoma tumors and associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why the genetic compromise of p16 predisposes to melanoma over other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Expression of p16 was rapidly upregulated following ultraviolet-irradiation and in response to H2 O2 -induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using small interfering RNA increased intracellular reactive oxygen species (ROS) and oxidative (8-oxoguanine) DNA damage, which was further enhanced by H2O2 treatment. Elevated ROS levels were also observed in p16-depleted human keratinocytes and in whole skin and dermal fibroblasts from Cdkn2a-deficient mice. Aberrant ROS and p38 signaling in Cdkn2a-deficient fibroblasts was normalized by expression of exogenous p16. The effect of p16 depletion on ROS was not recapitulated by the knockdown of retinoblastoma protein (Rb) and did not require Rb. Finally, p16-mediated suppression of ROS could not be attributed to the potential effects of p16 on cell cycle phase. These findings suggest a potential alternate Rb-independent tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. Compared with keratinocytes and fibroblasts, we also found increased susceptibility of melanocytes to oxidative stress in the context of p16 depletion, which may explain why the compromise of p16 predisposes to melanoma over other cancers.

Original languageEnglish (US)
Pages (from-to)265-274
Number of pages10
JournalOncogene
Volume30
Issue number3
DOIs
StatePublished - Jan 20 2011
Externally publishedYes

Keywords

  • 8-oxoguanine
  • melanocyte
  • oxidative stress
  • p16

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Jenkins, N. C., Liu, T., Cassidy, P., Leachman, S. A., Boucher, K. M., Goodson, A. G., Samadashwily, G., & Grossman, D. (2011). The p16 INK4A tumor suppressor regulates cellular oxidative stress. Oncogene, 30(3), 265-274. https://doi.org/10.1038/onc.2010.419