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.

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.

Aging Skin: Nourishing from the Inside Out, Effects of Good Versus Poor Nitrogen Intake on Skin Health and Healing

“…At the molecular level, it has been shown [33] that ultraviolet radiation (probably the most important factor responsible for extrinsic skin aging) is capable of modulating MMP induction through the activation of growth factor receptors on fibroblasts and keratinocytes. The activated epidermal growth factor receptor (EGFR), through the GTP-binding regulatory protein p21Ras, mediates the activation of the MAP kinase signal transduction, which activates ERK, JNK, and p38MAPK.…”

Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

“…This receptor was targeted because it has previously been identified in pterygia 33,34 and at least one of its ligands, HB-EGF, 8,35 has been linked with the pathogenesis of this disease. In addition, the EGFR is activated in the human skin in response to UVB, 27 and both HB-EGF and EGF can activate ERK1/2. 40,41 Initially, the expression of the EGFR was confirmed in several pterygium specimens (n ϭ 5).…”

“…9 In the context of pterygium development, these findings are relevant because activation of the ERK pathway can promote cell survival and proliferation, whereas activation of JNK and p38 signaling pathways can result in apoptosis. 26 Furthermore, the induction of MMP-1 by UVB, 27,28 UVA, 29 and possibly infrared-A radiation 30 is dependent on AP-1 (c-jun/c-fos) transcriptional activity that is downstream of ERK.…”

Photoaging of human skin

“…In vitro and in vivo studies have recently demonstrated that all-trans retinoic acid, which is a known transrepressor of the photoaging-involved transcription factor AP-1, when applied before UVB irradiation substantially abrogated the induction of AP-1 and MMPs. This abrogation was achieved in a posttranscriptional mechanism in which RA antagonized AP-1 activation by inhibition of c-jun protein induction (26). Subsequent work by the same group indicated that ultraviolet radiation causes a functional vitamin A deficiency and that this deficiency could be overcome by pretreating the skin with RA.…”