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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.
J Clin Invest. 1998 Mar 15; 101(6):1432-40.JCI

Abstract

Human skin is exposed daily to solar ultraviolet (UV) radiation. UV induces 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-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases. We investigated upstream signal transduction pathways and the mechanism 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 p21Ras, and stimulated mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38. Both JNK and p38 phosphorylated, and thereby activated transcription factors c-Jun and activating transcription factor 2 (ATF-2), which 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 protein 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 posttranscriptional mechanism by which tRA antagonizes UV activation of AP-1 by inhibiting c-Jun protein induction. Inhibition of c-Jun induction likely contributes to the previously reported prevention by tRA of UV induction of AP-1-regulated matrix-degrading metalloproteinases in human skin.

Authors+Show Affiliations

Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0609, USA. dianemch@umich.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9502786

Citation

Fisher, G J., et al. "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." The Journal of Clinical Investigation, vol. 101, no. 6, 1998, pp. 1432-40.
Fisher GJ, Talwar HS, Lin J, et al. 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. J Clin Invest. 1998;101(6):1432-40.
Fisher, G. J., Talwar, H. S., Lin, J., Lin, P., McPhillips, F., Wang, Z., Li, X., Wan, Y., Kang, S., & Voorhees, J. J. (1998). 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. The Journal of Clinical Investigation, 101(6), 1432-40.
Fisher GJ, et al. 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. J Clin Invest. 1998 Mar 15;101(6):1432-40. PubMed PMID: 9502786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Fisher,G J, AU - Talwar,H S, AU - Lin,J, AU - Lin,P, AU - McPhillips,F, AU - Wang,Z, AU - Li,X, AU - Wan,Y, AU - Kang,S, AU - Voorhees,J J, PY - 1998/4/29/pubmed PY - 1998/4/29/medline PY - 1998/4/29/entrez SP - 1432 EP - 40 JF - The Journal of clinical investigation JO - J Clin Invest VL - 101 IS - 6 N2 - Human skin is exposed daily to solar ultraviolet (UV) radiation. UV induces 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-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases. We investigated upstream signal transduction pathways and the mechanism 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 p21Ras, and stimulated mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38. Both JNK and p38 phosphorylated, and thereby activated transcription factors c-Jun and activating transcription factor 2 (ATF-2), which 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 protein 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 posttranscriptional mechanism by which tRA antagonizes UV activation of AP-1 by inhibiting c-Jun protein induction. Inhibition of c-Jun induction likely contributes to the previously reported prevention by tRA of UV induction of AP-1-regulated matrix-degrading metalloproteinases in human skin. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/9502786/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_ DB - PRIME DP - Unbound Medicine ER -