title: Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage.
abstract: Vitiligo 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.
authors.affiliation: Clinical and Experimental Dermatology, Department of Biomedical Sciences/Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, UK.
authors.forename: Mohamed M A E L
authors.initials: MM
authors.lastname: Salem
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shalbaf
authors.forename: Nicholas C J
authors.initials: NC
authors.lastname: Gibbons
authors.forename: Bhaven
authors.initials: B
authors.lastname: Chavan
authors.forename: J M
authors.initials: JM
authors.lastname: Thornton
authors.forename: Karin U
authors.initials: KU
authors.lastname: Schallreuter
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D053148:Caspase 3 / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008875:Middle Aged; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D030421:Peroxynitrous Acid / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D014820:Vitiligo / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D053148:Caspase 3; D018797:Cell Cycle Proteins; D045304:Cytochromes c; D004247:DNA; D004268:DNA-Binding Proteins; D006151:Guanosine; D006861:Hydrogen Peroxide; D030421:Peroxynitrous Acid; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C046215:8-hydroxyguanosine; C576324:ATM protein, human