RETINOIC ACID INHIBITS INDUCTION OF C-JUN PROTEIN BY ULTRAVIOLET-RADIATION THAT OCCURS SUBSEQUENT TO ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAYS IN HUMAN SKIN IN-VIVO

Human skin is exposed daily to solar ultraviolet (UV) radiation, UV in duces the matrix metalloproteinases collagenase, 92-kD gelatinase, and stromelysin, which degrade skin connective tissue and may contribute to premature skin aging (photoaging), Pretreatment of skin with all-tr ans retinoic acid (tRA) inhibits UV induction of matrix metalloprotein ases, We investigated upstream signal transduction pathways and the me chanism of tRA inhibition of UV induction of matrix metalloproteinases in human skin in vivo, Exposure of human skin in vivo to low doses of UV activated EGF receptors, the GTP-binding regulatory protein p(21)R as, and stimulated mitogen-activated protein (MAP) kinases, extracellu lar signal-regulated kinase (ERE;), c-Jun aminoterminal kinase (JNK), and p38, Both JNK and p38 phosphorylated, and thereby activated transc ription factors c-Jun and activating transcription factor 2 (ATF-2), w hich bound to the c-Jun promoter and upregulated c-Jun gene expression , Elevated c-Jun, in association with constitutively expressed c-Fos, formed increased levels of transcription factor activator protein (AP) 1, which is required for transcription of matrix metalloproteinases, Pretreatment of human skin with tRA inhibited UV induction of c-Jun pr otein and, consequently, AP-1, c-Jun protein inhibition occurred via a posttranscriptional mechanism, since tRA did not inhibit UV induction of c-Jun mRNA, These data demonstrate, for the first time, activation of MAP kinase pathways in humans in vivo, and reveal a novel posttran scriptional mechanism by which tRA antagonizes UV activation of AP-1 b y inhibiting c-Jun protein induction. Inhibition of c-Jun induction li kely contributes to the previously reported prevention by tRA of UV in duction of AP-1-regulated matrix-degrading metalloproteinases in human skin.