title: Regulation of ultraviolet B radiation-mediated activation of AP1 signaling by retinoids in primary keratinocytes.
abstract: The main cause of skin cancer and photo-aging is chronic exposure to ultraviolet B (UVB) radiation. Such damage can be ameliorated by retinoid treatment. UVB-radiation-induced skin carcinogenesis is associated with the induction of activator protein 1 (AP1) signaling and factors, namely FOS and JUN family members. We investigated the effects of several retinoids, all-trans-retinoic acid (tRA), 9-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl)-retinamide (HPR), on UVB-induced damage in primary mouse keratinocytes. In addition, the interplay between UVB radiation, retinoid receptors, and AP1 signaling was assessed using Western blot analysis and ribonuclease protection and gene reporter assays. Exposure of keratinocytes to UVB radiation caused a down-regulation of the retinoid receptor protein levels in a proteasome-mediated manner. In contrast, FOS and JUN proteins were transiently induced shortly after exposure to UVB radiation. Retinoid treatment caused a dose-dependent reduction in the levels of retinoid receptor proteins. When irradiated cells were treated with retinoids, no significant effects on AP1 protein expression were noted. Interestingly, pretreatments with tRA and cRA, but not HPR, suppressed UVB-radiation-induced AP1 activity by more than 50%, whereas post-treatment failed to produce similar effects. Our findings indicate that the inhibition of AP1 activity by retinoids explains, at least in part, the chemopreventive potential of retinoids in UV-radiation-associated epidermal damage.
authors.affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon. darwichn@aub.edu.lb
authors.forename: Nadine
authors.initials: N
authors.lastname: Darwiche
authors.forename: Hisham
authors.initials: H
authors.lastname: Bazzi
authors.forename: Lara
authors.initials: L
authors.lastname: El-Touni
authors.forename: Ghada
authors.initials: G
authors.lastname: Abou-Lteif
authors.forename: Rami
authors.initials: R
authors.lastname: Doueiri
authors.forename: Asma
authors.initials: A
authors.lastname: Hatoum
authors.forename: Samar
authors.initials: S
authors.lastname: Maalouf
authors.forename: Hala
authors.initials: H
authors.lastname: Gali-Muhtasib
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism; D017313:Fenretinide / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012176:Retinoids; D018808:Transcription Factor AP-1; D017313:Fenretinide; D014212:Tretinoin; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex