title: Role of melanin in melanocyte dysregulation of reactive oxygen species.
abstract: We have recently reported a potential alternative tumor suppressor function for p16 relating to its capacity to regulate oxidative stress and observed that oxidative dysregulation in p16-depleted cells was most profound in melanocytes, compared to keratinocytes or fibroblasts. Moreover, in the absence of p16 depletion or exogenous oxidative insult, melanocytes exhibited significantly higher basal levels of reactive oxygen species (ROS) than these other epidermal cell types. Given the role of oxidative stress in melanoma development, we speculated that this increased susceptibility of melanocytes to oxidative stress (and greater reliance on p16 for suppression of ROS) may explain why genetic compromise of p16 is more commonly associated with predisposition to melanoma rather than other cancers. Here we show that the presence of melanin accounts for this differential oxidative stress in normal and p16-depleted melanocytes. Thus the presence of melanin in the skin appears to be a double-edged sword: it protects melanocytes as well as neighboring keratinocytes in the skin through its capacity to absorb UV radiation, but its synthesis in melanocytes results in higher levels of intracellular ROS that may increase melanoma susceptibility.
authors.affiliation: Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
authors.forename: Noah C
authors.initials: NC
authors.lastname: Jenkins
authors.forename: Douglas
authors.initials: D
authors.lastname: Grossman
mesh_terms: D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis* / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D025803:Tumor Suppressor Protein p14ARF; D014466:Ultraviolet Rays
chemical_list: D008543:Melanins; D017382:Reactive Oxygen Species; D025803:Tumor Suppressor Protein p14ARF
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4111-5
references.pmid: 16537493
references.citation: Curr Opin Genet Dev. 1999 Feb;9(1):22-30
references.pmid: 10072356
references.citation: Eur J Cancer. 2004 Jun;40(9):1423-30
references.pmid: 15177503
references.citation: Biochim Biophys Acta. 1994 Apr 28;1221(3):272-8
references.pmid: 8167148
references.citation: Oncogene. 2011 Jan 20;30(3):265-74
references.pmid: 20838381
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12180-5
references.pmid: 20566850
references.citation: Int J Biochem Cell Biol. 1997 Nov;29(11):1235-9
references.pmid: 9451820
references.citation: Clin Cancer Res. 2007 Oct 1;13(19):5952-8
references.pmid: 17908992
references.citation: Cancer Res. 2002 Nov 15;62(22):6724-30
references.pmid: 12438273
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13742-7
references.pmid: 8943005