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. 1998 Mar 15;101(6):1432–1440. doi: 10.1172/JCI2153

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.

G J Fisher 1, H S Talwar 1, J Lin 1, P Lin 1, F McPhillips 1, Z Wang 1, X Li 1, Y Wan 1, S Kang 1, J J Voorhees 1
PMCID: PMC508699  PMID: 9502786

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.

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Selected References

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  1. Bender K., Blattner C., Knebel A., Iordanov M., Herrlich P., Rahmsdorf H. J. UV-induced signal transduction. J Photochem Photobiol B. 1997 Jan;37(1-2):1–17. doi: 10.1016/s1011-1344(96)07459-3. [DOI] [PubMed] [Google Scholar]
  2. Cavigelli M., Dolfi F., Claret F. X., Karin M. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J. 1995 Dec 1;14(23):5957–5964. doi: 10.1002/j.1460-2075.1995.tb00284.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chen J. Y., Penco S., Ostrowski J., Balaguer P., Pons M., Starrett J. E., Reczek P., Chambon P., Gronemeyer H. RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage-independent cell proliferation. EMBO J. 1995 Mar 15;14(6):1187–1197. doi: 10.1002/j.1460-2075.1995.tb07102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Claret F. X., Hibi M., Dhut S., Toda T., Karin M. A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature. 1996 Oct 3;383(6599):453–457. doi: 10.1038/383453a0. [DOI] [PubMed] [Google Scholar]
  5. Coso O. A., Chiariello M., Yu J. C., Teramoto H., Crespo P., Xu N., Miki T., Gutkind J. S. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995 Jun 30;81(7):1137–1146. doi: 10.1016/s0092-8674(05)80018-2. [DOI] [PubMed] [Google Scholar]
  6. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  7. Deng T., Karin M. JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers. Genes Dev. 1993 Mar;7(3):479–490. doi: 10.1101/gad.7.3.479. [DOI] [PubMed] [Google Scholar]
  8. Denhardt D. T. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. Biochem J. 1996 Sep 15;318(Pt 3):729–747. doi: 10.1042/bj3180729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fisher G. J., Datta S. C., Talwar H. S., Wang Z. Q., Varani J., Kang S., Voorhees J. J. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature. 1996 Jan 25;379(6563):335–339. doi: 10.1038/379335a0. [DOI] [PubMed] [Google Scholar]
  10. Fisher G. J., Esmann J., Griffiths C. E., Talwar H. S., Duell E. A., Hammerberg C., Elder J. T., Finkel L. J., Karabin G. D., Nickoloff B. J. Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin. J Invest Dermatol. 1991 May;96(5):699–707. doi: 10.1111/1523-1747.ep12470632. [DOI] [PubMed] [Google Scholar]
  11. Fisher G. J., Reddy A. P., Datta S. C., Kang S., Yi J. Y., Chambon P., Voorhees J. J. All-trans retinoic acid induces cellular retinol-binding protein in human skin in vivo. J Invest Dermatol. 1995 Jul;105(1):80–86. doi: 10.1111/1523-1747.ep12313352. [DOI] [PubMed] [Google Scholar]
  12. Fisher G. J., Talwar H. S., Xiao J. H., Datta S. C., Reddy A. P., Gaub M. P., Rochette-Egly C., Chambon P., Voorhees J. J. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem. 1994 Aug 12;269(32):20629–20635. [PubMed] [Google Scholar]
  13. Fisher G. J., Wang Z. Q., Datta S. C., Varani J., Kang S., Voorhees J. J. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med. 1997 Nov 13;337(20):1419–1428. doi: 10.1056/NEJM199711133372003. [DOI] [PubMed] [Google Scholar]
  14. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  15. Hibi M., Lin A., Smeal T., Minden A., Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. doi: 10.1101/gad.7.11.2135. [DOI] [PubMed] [Google Scholar]
  16. Huang R. P., Wu J. X., Fan Y., Adamson E. D. UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol. 1996 Apr;133(1):211–220. doi: 10.1083/jcb.133.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Johnson N. L., Gardner A. M., Diener K. M., Lange-Carter C. A., Gleavy J., Jarpe M. B., Minden A., Karin M., Zon L. I., Johnson G. L. Signal transduction pathways regulated by mitogen-activated/extracellular response kinase kinase kinase induce cell death. J Biol Chem. 1996 Feb 9;271(6):3229–3237. doi: 10.1074/jbc.271.6.3229. [DOI] [PubMed] [Google Scholar]
  18. Karin M., Hunter T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr Biol. 1995 Jul 1;5(7):747–757. doi: 10.1016/s0960-9822(95)00151-5. [DOI] [PubMed] [Google Scholar]
  19. Lavker R. M., Veres D. A., Irwin C. J., Kaidbey K. H. Quantitative assessment of cumulative damage from repetitive exposures to suberythemogenic doses of UVA in human skin. Photochem Photobiol. 1995 Aug;62(2):348–352. doi: 10.1111/j.1751-1097.1995.tb05280.x. [DOI] [PubMed] [Google Scholar]
  20. Lohnes D., Mark M., Mendelsohn C., Dollé P., Decimo D., LeMeur M., Dierich A., Gorry P., Chambon P. Developmental roles of the retinoic acid receptors. J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):475–486. doi: 10.1016/0960-0760(95)00094-g. [DOI] [PubMed] [Google Scholar]
  21. Minden A., Lin A., Claret F. X., Abo A., Karin M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell. 1995 Jun 30;81(7):1147–1157. doi: 10.1016/s0092-8674(05)80019-4. [DOI] [PubMed] [Google Scholar]
  22. Minden A., Lin A., Smeal T., Dérijard B., Cobb M., Davis R., Karin M. c-Jun N-terminal phosphorylation correlates with activation of the JNK subgroup but not the ERK subgroup of mitogen-activated protein kinases. Mol Cell Biol. 1994 Oct;14(10):6683–6688. doi: 10.1128/mcb.14.10.6683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Musti A. M., Treier M., Bohmann D. Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases. Science. 1997 Jan 17;275(5298):400–402. doi: 10.1126/science.275.5298.400. [DOI] [PubMed] [Google Scholar]
  24. Pfahl M. Nuclear receptor/AP-1 interaction. Endocr Rev. 1993 Oct;14(5):651–658. doi: 10.1210/edrv-14-5-651. [DOI] [PubMed] [Google Scholar]
  25. Pfarr C. M., Mechta F., Spyrou G., Lallemand D., Carillo S., Yaniv M. Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell. 1994 Feb 25;76(4):747–760. doi: 10.1016/0092-8674(94)90513-4. [DOI] [PubMed] [Google Scholar]
  26. Raingeaud J., Gupta S., Rogers J. S., Dickens M., Han J., Ulevitch R. J., Davis R. J. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995 Mar 31;270(13):7420–7426. doi: 10.1074/jbc.270.13.7420. [DOI] [PubMed] [Google Scholar]
  27. Rosette C., Karin M. Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science. 1996 Nov 15;274(5290):1194–1197. doi: 10.1126/science.274.5290.1194. [DOI] [PubMed] [Google Scholar]
  28. Rozek D., Pfeifer G. P. In vivo protein-DNA interactions at the c-jun promoter: preformed complexes mediate the UV response. Mol Cell Biol. 1993 Sep;13(9):5490–5499. doi: 10.1128/mcb.13.9.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sachsenmaier C., Radler-Pohl A., Zinck R., Nordheim A., Herrlich P., Rahmsdorf H. J. Involvement of growth factor receptors in the mammalian UVC response. Cell. 1994 Sep 23;78(6):963–972. doi: 10.1016/0092-8674(94)90272-0. [DOI] [PubMed] [Google Scholar]
  30. Scheele J. S., Rhee J. M., Boss G. R. Determination of absolute amounts of GDP and GTP bound to Ras in mammalian cells: comparison of parental and Ras-overproducing NIH 3T3 fibroblasts. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1097–1100. doi: 10.1073/pnas.92.4.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schüle R., Rangarajan P., Yang N., Kliewer S., Ransone L. J., Bolado J., Verma I. M., Evans R. M. Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6092–6096. doi: 10.1073/pnas.88.14.6092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Talwar H. S., Griffiths C. E., Fisher G. J., Hamilton T. A., Voorhees J. J. Reduced type I and type III procollagens in photodamaged adult human skin. J Invest Dermatol. 1995 Aug;105(2):285–290. doi: 10.1111/1523-1747.ep12318471. [DOI] [PubMed] [Google Scholar]
  33. Tavakkol A., Zouboulis C. C., Duell E. A., Voorhees J. J. A retinoic acid-inducible skin-specific gene (RIS-1/psoriasin): molecular cloning and analysis of gene expression in human skin in vivo and cultured skin cells in vitro. Mol Biol Rep. 1994;20(2):75–83. doi: 10.1007/BF00996356. [DOI] [PubMed] [Google Scholar]
  34. Treier M., Staszewski L. M., Bohmann D. Ubiquitin-dependent c-Jun degradation in vivo is mediated by the delta domain. Cell. 1994 Sep 9;78(5):787–798. doi: 10.1016/s0092-8674(94)90502-9. [DOI] [PubMed] [Google Scholar]
  35. Tremble P., Damsky C. H., Werb Z. Components of the nuclear signaling cascade that regulate collagenase gene expression in response to integrin-derived signals. J Cell Biol. 1995 Jun;129(6):1707–1720. doi: 10.1083/jcb.129.6.1707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  37. Warmuth I., Harth Y., Matsui M. S., Wang N., DeLeo V. A. Ultraviolet radiation induces phosphorylation of the epidermal growth factor receptor. Cancer Res. 1994 Jan 15;54(2):374–376. [PubMed] [Google Scholar]
  38. Weber J. D., Raben D. M., Phillips P. J., Baldassare J. J. Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J. 1997 Aug 15;326(Pt 1):61–68. doi: 10.1042/bj3260061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Whitmarsh A. J., Davis R. J. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl) 1996 Oct;74(10):589–607. doi: 10.1007/s001090050063. [DOI] [PubMed] [Google Scholar]
  40. Zheng C. F., Guan K. L. Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem. 1993 Nov 15;268(32):23933–23939. [PubMed] [Google Scholar]
  41. van Dam H., Wilhelm D., Herr I., Steffen A., Herrlich P., Angel P. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J. 1995 Apr 18;14(8):1798–1811. doi: 10.1002/j.1460-2075.1995.tb07168.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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