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EMBO J. 1995 Dec 1; 14(23): 5957–5964.
doi: 10.1002/j.1460-2075.1995.tb00284.x
PMCID: PMC394715
PMID: 8846788

Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation.

M Cavigelli, F Dolfi, F X Claret, and M Karin
Author information Copyright and License information PMC Disclaimer

Abstract

Growth factors induce c-fos transcription by stimulating phosphorylation of transcription factor TCF/Elk-1, which binds to the serum response element (SRE). Under such conditions Elk-1 could be phosphorylated by the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2. However, c-fos transcription and SRE activity are also induced by stimuli, such as UV irradiation and activation of the protein kinase MEKK1, that cause only an insignificant increase in ERK1/2 activity. However, both of these stimuli strongly activate two other MAPKs, JNK1 and JNK2, and stimulate Elk-1 transcriptional activity and phosphorylation. We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. Finally, we show that UV irradiation, but not serum or phorbol esters, stimulate translocation of JNK1 to the nucleus. As Elk-1 is most likely phosphorylated while bound to the c-fos promoter, these results suggest that UV irradiation and MEKK1 activation stimulate TCF/Elk-1 activity through JNK activation, while growth factors induce c-fos through ERK activation.

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Selected References

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  • Boyle WJ, van der Geer P, Hunter T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 1991;201:110–149. [PubMed] [Google Scholar]
  • Büscher M, Rahmsdorf HJ, Litfin M, Karin M, Herrlich P. Activation of the c-fos gene by UV and phorbol ester: different signal transduction pathways converge to the same enhancer element. Oncogene. 1988 Sep;3(3):301–311. [PubMed] [Google Scholar]
  • Darnell JE, Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. [PubMed] [Google Scholar]
  • 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] [Google Scholar]
  • Dérijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. [PubMed] [Google Scholar]
  • Devary Y, Gottlieb RA, Lau LF, Karin M. Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol Cell Biol. 1991 May;11(5):2804–2811. [PMC free article] [PubMed] [Google Scholar]
  • DiDonato JA, Mercurio F, Karin M. Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B. Mol Cell Biol. 1995 Mar;15(3):1302–1311. [PMC free article] [PubMed] [Google Scholar]
  • Gille H, Sharrocks AD, Shaw PE. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature. 1992 Jul 30;358(6385):414–417. [PubMed] [Google Scholar]
  • Gille H, Kortenjann M, Thomae O, Moomaw C, Slaughter C, Cobb MH, Shaw PE. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J. 1995 Mar 1;14(5):951–962. [PMC free article] [PubMed] [Google Scholar]
  • Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus. J Cell Biol. 1993 Sep;122(5):1089–1101. [PMC free article] [PubMed] [Google Scholar]
  • Gupta S, Campbell D, Dérijard B, Davis RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. [PubMed] [Google Scholar]
  • Hayes TE, Kitchen AM, Cochran BH. Inducible binding of a factor to the c-fos regulatory region. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1272–1276. [PMC free article] [PubMed] [Google Scholar]
  • Herrera RE, Shaw PE, Nordheim A. Occupation of the c-fos serum response element in vivo by a multi-protein complex is unaltered by growth factor induction. Nature. 1989 Jul 6;340(6228):68–70. [PubMed] [Google Scholar]
  • 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] [Google Scholar]
  • Hill CS, Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. [PubMed] [Google Scholar]
  • Hill CS, Marais R, John S, Wynne J, Dalton S, Treisman R. Functional analysis of a growth factor-responsive transcription factor complex. Cell. 1993 Apr 23;73(2):395–406. [PubMed] [Google Scholar]
  • Hipskind RA, Rao VN, Mueller CG, Reddy ES, Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991 Dec 19;354(6354):531–534. [PubMed] [Google Scholar]
  • Kallunki T, Su B, Tsigelny I, Sluss HK, Dérijard B, Moore G, Davis R, Karin M. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 1994 Dec 15;8(24):2996–3007. [PubMed] [Google Scholar]
  • 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. [PubMed] [Google Scholar]
  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. [PubMed] [Google Scholar]
  • Lenormand P, Sardet C, Pagès G, L'Allemain G, Brunet A, Pouysségur J. Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol. 1993 Sep;122(5):1079–1088. [PMC free article] [PubMed] [Google Scholar]
  • Lillie JW, Green MR. Transcription activation by the adenovirus E1a protein. Nature. 1989 Mar 2;338(6210):39–44. [PubMed] [Google Scholar]
  • Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. [PubMed] [Google Scholar]
  • Livingstone C, Patel G, Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995 Apr 18;14(8):1785–1797. [PMC free article] [PubMed] [Google Scholar]
  • Marais R, Wynne J, Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. [PubMed] [Google Scholar]
  • Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. [PubMed] [Google Scholar]
  • Meyer TE, Habener JF. Cyclic adenosine 3',5'-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev. 1993 Jun;14(3):269–290. [PubMed] [Google Scholar]
  • Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis RJ, Johnson GL, Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. [PubMed] [Google Scholar]
  • 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. [PMC free article] [PubMed] [Google Scholar]
  • Price MA, Rogers AE, Treisman R. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET). EMBO J. 1995 Jun 1;14(11):2589–2601. [PMC free article] [PubMed] [Google Scholar]
  • 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] [Google Scholar]
  • Rivera VM, Miranti CK, Misra RP, Ginty DD, Chen RH, Blenis J, Greenberg ME. A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity. Mol Cell Biol. 1993 Oct;13(10):6260–6273. [PMC free article] [PubMed] [Google Scholar]
  • 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] [Google Scholar]
  • Sánchez I, Hughes RT, Mayer BJ, Yee K, Woodgett JR, Avruch J, Kyriakis JM, Zon LI. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. [PubMed] [Google Scholar]
  • Schreiber M, Baumann B, Cotten M, Angel P, Wagner EF. Fos is an essential component of the mammalian UV response. EMBO J. 1995 Nov 1;14(21):5338–5349. [PMC free article] [PubMed] [Google Scholar]
  • Storrie B, Madden EA. Isolation of subcellular organelles. Methods Enzymol. 1990;182:203–225. [PubMed] [Google Scholar]
  • Su B, Jacinto E, Hibi M, Kallunki T, Karin M, Ben-Neriah Y. JNK is involved in signal integration during costimulation of T lymphocytes. Cell. 1994 Jun 3;77(5):727–736. [PubMed] [Google Scholar]
  • Treisman R. The serum response element. Trends Biochem Sci. 1992 Oct;17(10):423–426. [PubMed] [Google Scholar]
  • van Dam H, Duyndam M, Rottier R, Bosch A, de Vries-Smits L, Herrlich P, Zantema A, Angel P, van der Eb AJ. Heterodimer formation of cJun and ATF-2 is responsible for induction of c-jun by the 243 amino acid adenovirus E1A protein. EMBO J. 1993 Feb;12(2):479–487. [PMC free article] [PubMed] [Google Scholar]
  • 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. [PMC free article] [PubMed] [Google Scholar]
  • Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ. Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature. 1994 Dec 22;372(6508):798–800. [PubMed] [Google Scholar]
  • Zinck R, Hipskind RA, Pingoud V, Nordheim A. c-fos transcriptional activation and repression correlate temporally with the phosphorylation status of TCF. EMBO J. 1993 Jun;12(6):2377–2387. [PMC free article] [PubMed] [Google Scholar]
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