Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage
AuthorSalem, Mohamed M.A.
Gibbons, Nick C.
Thornton, M. Julie
Schallreuter, Karin U.
Ataxia Telangiectasia Mutated Proteins
Caspase 3; Biosynthesis
Cell cycle proteins; Metabolism
DNA damage; Drug effects
Electrophoretic mobility shift assay
Guanosine; Analogs & derivatives
Hydrogen peroxide; Pharmacology
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-mdm2
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
p300-CBP Transcription Factors
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AbstractVitiligo is characterized by a patchy loss of inherited skin color affecting approximately 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H(2)O(2))-induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun-induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8-oxoguanine in the skin and plasma in association with epidermal up-regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76(MDM2). Short-patch base-excision repair via hOgg1, APE1, and polymerasebeta DNA repair is up-regulated. Overexpression of Bcl-2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO(-)) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO(-) (300 x 10(-6) M) abrogates DNA binding, while H(2)O(2)-oxidized p53 (10(-3) M) enhances DNA binding capacity and prevents ONOO(-)-induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we propose up-regulated wild-type p53 together with p76(MDM2) as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.
CitationSalem, M. M., Shalbaf, M., Gibbons, N. C., Chavan, B., Thornton, J. M., Schallreuter, K. U. (2009) Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage. FASEB Journal, 23(11), 3790-3807.
Link to publisher’s versionhttp://dx.doi.org/10.1096/fj.09-132621
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