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J Cell Biol. 1996 Apr 1; 133(1): 211–220.
PMCID: PMC2120786

UV activates growth factor receptors via reactive oxygen intermediates


Exposure of mammalian cells to UV irradiation induces rapid and transient expression of early growth response-1 gene (Egr-1) encoding a transcription factor that plays a role in cell survival. These signals from the irradiated cell surface are likely to involve more than one pathway, and we show here that an essential pathway involves activation of several growth factor receptors by reactive oxygen intermediates (ROI). UVC irradiation causes the tyrosine phosphorylation of EGF receptor (EGFR) in mouse NIH 3T3 fibroblasts and HC11 mouse mammary cells. EGFR activation by irradiation of cells is abrogated by suramin, by antioxidants, and by the presence of a dominant negative EGFR. UV induces the formation of complexes between activated EGFR and SOS, Grb2, PLC gamma, and SHC that can be precipitated with antibodies to EGFR. The activation of EGFR by UV is mimicked by H2O2, suggesting that ROI may function upstream of EGFR activation. Our observations support the hypothesis that ROI and growth factor receptors operate in the early steps of the UV signal that lead to the enhanced expression and activity of Egr-1.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ball RK, Friis RR, Schoenenberger CA, Doppler W, Groner B. Prolactin regulation of beta-casein gene expression and of a cytosolic 120-kd protein in a cloned mouse mammary epithelial cell line. EMBO J. 1988 Jul;7(7):2089–2095. [PMC free article] [PubMed]
  • Batzer AG, Rotin D, Ureña JM, Skolnik EY, Schlessinger J. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol Cell Biol. 1994 Aug;14(8):5192–5201. [PMC free article] [PubMed]
  • Betsholtz C, Johnsson A, Heldin CH, Westermark B. Efficient reversion of simian sarcoma virus-transformation and inhibition of growth factor-induced mitogenesis by suramin. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6440–6444. [PMC free article] [PubMed]
  • Brown SB, Krause D, Ellem KA. Low fluences of ultraviolet irradiation stimulate HeLa cell surface aminopeptidase and candidate "TGF alpha ase" activity. J Cell Biochem. 1993 Jan;51(1):102–115. [PubMed]
  • Chenevix-Trench G, Cullinan M, Ellem KA, Hayward NK. UV induction of transforming growth factor alpha in melanoma cell lines is a posttranslational event. J Cell Physiol. 1992 Aug;152(2):328–336. [PubMed]
  • Coffer PJ, Burgering BM, Peppelenbosch MP, Bos JL, Kruijer W. UV activation of receptor tyrosine kinase activity. Oncogene. 1995 Aug 3;11(3):561–569. [PubMed]
  • Danielson KG, Oborn CJ, Durban EM, Butel JS, Medina D. Epithelial mouse mammary cell line exhibiting normal morphogenesis in vivo and functional differentiation in vitro. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3756–3760. [PMC free article] [PubMed]
  • Datta R, Rubin E, Sukhatme V, Qureshi S, Hallahan D, Weichselbaum RR, Kufe DW. Ionizing radiation activates transcription of the EGR1 gene via CArG elements. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10149–10153. [PMC free article] [PubMed]
  • Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. [PubMed]
  • Devary Y, Gottlieb RA, Smeal T, Karin M. The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell. 1992 Dec 24;71(7):1081–1091. [PubMed]
  • Devary Y, Rosette C, DiDonato JA, Karin M. NF-kappa B activation by ultraviolet light not dependent on a nuclear signal. Science. 1993 Sep 10;261(5127):1442–1445. [PubMed]
  • Engelberg D, Klein C, Martinetto H, Struhl K, Karin M. The UV response involving the Ras signaling pathway and AP-1 transcription factors is conserved between yeast and mammals. Cell. 1994 May 6;77(3):381–390. [PubMed]
  • Fialkow L, Chan CK, Rotin D, Grinstein S, Downey GP. Activation of the mitogen-activated protein kinase signaling pathway in neutrophils. Role of oxidants. J Biol Chem. 1994 Dec 9;269(49):31234–31242. [PubMed]
  • Fornace AJ, Jr, Jackman J, Hollander MC, Hoffman-Liebermann B, Liebermann DA. Genotoxic-stress-response genes and growth-arrest genes. gadd, MyD, and other genes induced by treatments eliciting growth arrest. Ann N Y Acad Sci. 1992 Nov 21;663:139–153. [PubMed]
  • Gergel JR, McNamara DJ, Dobrusin EM, Zhu G, Saltiel AR, Miller WT. Identification of amino acids in the N-terminal SH2 domain of phospholipase C gamma 1 important in the interaction with epidermal growth factor receptor. Biochemistry. 1994 Dec 13;33(49):14671–14678. [PubMed]
  • Godar DE, Thomas DP, Miller SA, Lee W. Long-wavelength UVA radiation induces oxidative stress, cytoskeletal damage and hemolysis. Photochem Photobiol. 1993 Jun;57(6):1018–1026. [PubMed]
  • Goossens V, Grooten J, De Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8115–8119. [PMC free article] [PubMed]
  • Henderson SA, Lee PH, Aeberhard EE, Adams JW, Ignarro LJ, Murphy WJ, Sherman MP. Nitric oxide reduces early growth response-1 gene expression in rat lung macrophages treated with interferon-gamma and lipopolysaccharide. J Biol Chem. 1994 Oct 14;269(41):25239–25242. [PubMed]
  • Herrlich P, Ponta H, Rahmsdorf HJ. DNA damage-induced gene expression: signal transduction and relation to growth factor signaling. Rev Physiol Biochem Pharmacol. 1992;119:187–223. [PubMed]
  • Herrlich P, Sachsenmaier C, Radler-Pohl A, Gebel S, Blattner C, Rahmsdorf HJ. The mammalian UV response: mechanism of DNA damage induced gene expression. Adv Enzyme Regul. 1994;34:381–395. [PubMed]
  • 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. [PubMed]
  • Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. [PubMed]
  • Huang RP, Adamson ED. The phosphorylated forms of the transcription factor, Egr-1, bind to DNA more efficiently than non-phosphorylated. Biochem Biophys Res Commun. 1994 May 16;200(3):1271–1276. [PubMed]
  • Huang RP, Adamson ED. A biological role for Egr-1 in cell survival following ultra-violet irradiation. Oncogene. 1995 Feb 2;10(3):467–475. [PubMed]
  • Huang RP, Darland T, Okamura D, Mercola D, Adamson ED. Suppression of v-sis-dependent transformation by the transcription factor, Egr-1. Oncogene. 1994 May;9(5):1367–1377. [PubMed]
  • Huang RP, Ngo L, Okamura D, Tucker M, Adamson ED. V-sis induces Egr-1 expression by a pathway mediated by c-Ha-Ras. J Cell Biochem. 1994 Dec;56(4):469–479. [PubMed]
  • Huang RP, Liu C, Fan Y, Mercola D, Adamson ED. Egr-1 negatively regulates human tumor cell growth via the DNA-binding domain. Cancer Res. 1995 Nov 1;55(21):5054–5062. [PubMed]
  • Krämer M, Sachsenmaier C, Herrlich P, Rahmsdorf HJ. UV irradiation-induced interleukin-1 and basic fibroblast growth factor synthesis and release mediate part of the UV response. J Biol Chem. 1993 Mar 25;268(9):6734–6741. [PubMed]
  • Kripke ML. Ultraviolet radiation and immunology: something new under the sun--presidential address. Cancer Res. 1994 Dec 1;54(23):6102–6105. [PubMed]
  • Lemaire P, Revelant O, Bravo R, Charnay P. Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4691–4695. [PMC free article] [PubMed]
  • Ley KD, Ellem KA. UVC modulation of epidermal growth factor receptor number in HeLa S3 cells. Carcinogenesis. 1992 Feb;13(2):183–187. [PubMed]
  • Lo YY, Cruz TF. Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. J Biol Chem. 1995 May 19;270(20):11727–11730. [PubMed]
  • Luna MC, Wong S, Gomer CJ. Photodynamic therapy mediated induction of early response genes. Cancer Res. 1994 Mar 1;54(5):1374–1380. [PubMed]
  • Marte BM, Jeschke M, Graus-Porta D, Taverna D, Hofer P, Groner B, Yarden Y, Hynes NE. Neu differentiation factor/heregulin modulates growth and differentiation of HC11 mammary epithelial cells. Mol Endocrinol. 1995 Jan;9(1):14–23. [PubMed]
  • May JM, de Haën C. The insulin-like effect of hydrogen peroxide on pathways of lipid synthesis in rat adipocytes. J Biol Chem. 1979 Sep 25;254(18):9017–9021. [PubMed]
  • Middaugh CR, Mach H, Burke CJ, Volkin DB, Dabora JM, Tsai PK, Bruner MW, Ryan JA, Marfia KE. Nature of the interaction of growth factors with suramin. Biochemistry. 1992 Sep 22;31(37):9016–9024. [PubMed]
  • Mohan N, Meltz ML. Induction of nuclear factor kappa B after low-dose ionizing radiation involves a reactive oxygen intermediate signaling pathway. Radiat Res. 1994 Oct;140(1):97–104. [PubMed]
  • Mukherjee SP, Mikherjee C, Yeager MD, Lynn WS. Stimulation of glucose transport and oxidation in adipocytes by fatty acids: evidence for a regulatory role in the cellular response to insulin. Biochem Biophys Res Commun. 1980 May 30;94(2):682–689. [PubMed]
  • Mukherjee SP, Mukherjee C, Lynn WS. Activation of pyruvate dehydrogenase in rat adipocytes by concanavalin A: evidence for insulin-like effect mediated by hydrogen peroxide. Biochem Biophys Res Commun. 1980 Mar 13;93(1):36–41. [PubMed]
  • Muroi M, Muroi Y, Suzuki T. The binding of immobilized IgG2a to Fc gamma 2a receptor activates NF-kappa B via reactive oxygen intermediates and tumor necrosis factor-alpha 1. J Biol Chem. 1994 Dec 2;269(48):30561–30568. [PubMed]
  • Murphy GM, Quinn DG, Camp RD, Hawk JL, Greaves MW. In-vivo studies of the action spectrum and time course for release of transforming growth factor-alpha by ultraviolet irradiation in man. Br J Dermatol. 1991 Dec;125(6):566–568. [PubMed]
  • Ohba M, Shibanuma M, Kuroki T, Nose K. Production of hydrogen peroxide by transforming growth factor-beta 1 and its involvement in induction of egr-1 in mouse osteoblastic cells. J Cell Biol. 1994 Aug;126(4):1079–1088. [PMC free article] [PubMed]
  • Orren DK, Petersen LN, Bohr VA. A UV-responsive G2 checkpoint in rodent cells. Mol Cell Biol. 1995 Jul;15(7):3722–3730. [PMC free article] [PubMed]
  • Pantopoulos K, Hentze MW. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 1995 Jun 15;14(12):2917–2924. [PMC free article] [PubMed]
  • Petersen LN, Orren DK, Bohr VA. Gene-specific and strand-specific DNA repair in the G1 and G2 phases of the cell cycle. Mol Cell Biol. 1995 Jul;15(7):3731–3737. [PMC free article] [PubMed]
  • Poste G. Enucleation of mammalian cells by cytochalasin B. I. Characterization of anucleate cells. Exp Cell Res. 1972 Aug;73(2):273–286. [PubMed]
  • Radler-Pohl A, Sachsenmaier C, Gebel S, Auer HP, Bruder JT, Rapp U, Angel P, Rahmsdorf HJ, Herrlich P. UV-induced activation of AP-1 involves obligatory extranuclear steps including Raf-1 kinase. EMBO J. 1993 Mar;12(3):1005–1012. [PMC free article] [PubMed]
  • Rao GN, Lassègue B, Griendling KK, Alexander RW. Hydrogen peroxide stimulates transcription of c-jun in vascular smooth muscle cells: role of arachidonic acid. Oncogene. 1993 Oct;8(10):2759–2764. [PubMed]
  • Repine JE, Pfenninger OW, Talmage DW, Berger EM, Pettijohn DE. Dimethyl sulfoxide prevents DNA nicking mediated by ionizing radiation or iron/hydrogen peroxide-generated hydroxyl radical. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1001–1003. [PMC free article] [PubMed]
  • Sachsenmaier C, Radler-Pohl A, Müller A, Herrlich P, Rahmsdorf HJ. Damage to DNA by UV light and activation of transcription factors. Biochem Pharmacol. 1994 Jan 13;47(1):129–136. [PubMed]
  • Sachsenmaier C, Radler-Pohl A, Zinck R, Nordheim A, Herrlich P, Rahmsdorf HJ. Involvement of growth factor receptors in the mammalian UVC response. Cell. 1994 Sep 23;78(6):963–972. [PubMed]
  • Schenk H, Klein M, Erdbrügger W, Dröge W, Schulze-Osthoff K. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1672–1676. [PMC free article] [PubMed]
  • Schieven GL, Mittler RS, Nadler SG, Kirihara JM, Bolen JB, Kanner SB, Ledbetter JA. ZAP-70 tyrosine kinase, CD45, and T cell receptor involvement in UV- and H2O2-induced T cell signal transduction. J Biol Chem. 1994 Aug 12;269(32):20718–20726. [PubMed]
  • Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. [PMC free article] [PubMed]
  • Schreck R, Albermann K, Baeuerle PA. Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Radic Res Commun. 1992;17(4):221–237. [PubMed]
  • Stein B, Rahmsdorf HJ, Steffen A, Litfin M, Herrlich P. UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein. Mol Cell Biol. 1989 Nov;9(11):5169–5181. [PMC free article] [PubMed]
  • Stevenson MA, Pollock SS, Coleman CN, Calderwood SK. X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res. 1994 Jan 1;54(1):12–15. [PubMed]
  • Sukhatme VP, Cao XM, Chang LC, Tsai-Morris CH, Stamenkovich D, Ferreira PC, Cohen DR, Edwards SA, Shows TB, Curran T, et al. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988 Apr 8;53(1):37–43. [PubMed]
  • Wang XQ, Ellem KA. Heterogeneity in the HeLa cell cycle response to UVC analyzed by the BrdUrd two-parameter method. Exp Cell Res. 1994 Jun;212(2):176–189. [PubMed]
  • Weller A, Meek J, Adamson ED. Preparation and properties of monoclonal and polyclonal antibodies to mouse epidermal growth factor (EGF) receptors: evidence for cryptic EGF receptors in embryonal carcinoma cells. Development. 1987 Jun;100(2):351–363. [PubMed]
  • Wu JX, Adamson ED. Inhibition of differentiation in P19 embryonal carcinoma cells by the expression of vectors encoding truncated or antisense EGF receptor. Dev Biol. 1993 Sep;159(1):208–222. [PubMed]
  • Zhan Q, Carrier F, Fornace AJ., Jr Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol Cell Biol. 1993 Jul;13(7):4242–4250. [PMC free article] [PubMed]

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