Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

The EMBO Journal logoLink to The EMBO Journal
. 1996 Dec 2;15(23):6552–6563.

The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c-fos transcription in response to UV light.

M A Price 1, F H Cruzalegui 1, R Treisman 1
PMCID: PMC452480  PMID: 8978682

Abstract

We investigated the activation of c-fos transcription following UV irradiation, a 'stress' stimulus. In both HeLa TK- and NIH 3T3 cells the Serum Response Element is required for efficient UV-induced c-fos transcription, and in HeLa TK- cells the Ternary Complex Factor (TCF) binding site contributes substantially to activation. Consistent with this, UV irradiation activates LexA-TCF fusion proteins more strongly in HeLa TK- than in NIH 3T3 cells. The TCF C-termini of the TCFs are substrates for UV-induced MAP kinases: both the Elk-1 and SAP-1a C-termini are efficiently phosphorylated by the p38 MAPK, but only the Elk-1 C-terminus is a good substrate for the SAPK/JNKs. The specificity and activation kinetics of TCF C-terminal kinases, and the susceptibility of transcriptional activation by LexA-TCF fusion proteins to specific inhibitors of different MAPK pathways, show that both the ERK and p38 MAPK pathways contribute to TCF activation in response to UV irradiation. Activity of both these pathways is also required for the response of the c-fos gene itself to UV stimulation.

Full text

PDF
6552

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler V., Franklin C. C., Kraft A. S. Phorbol esters stimulate the phosphorylation of c-Jun but not v-Jun: regulation by the N-terminal delta domain. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5341–5345. doi: 10.1073/pnas.89.12.5341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. doi: 10.1074/jbc.270.46.27489. [DOI] [PubMed] [Google Scholar]
  3. Bonni A., Ginty D. D., Dudek H., Greenberg M. E. Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals. Mol Cell Neurosci. 1995 Apr;6(2):168–183. doi: 10.1006/mcne.1995.1015. [DOI] [PubMed] [Google Scholar]
  4. Büscher M., Rahmsdorf H. J., 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]
  5. Cano E., Hazzalin C. A., Kardalinou E., Buckle R. S., Mahadevan L. C. Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction. J Cell Sci. 1995 Nov;108(Pt 11):3599–3609. doi: 10.1242/jcs.108.11.3599. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Coso O. A., Chiariello M., Kalinec G., Kyriakis J. M., Woodgett J., Gutkind J. S. Transforming G protein-coupled receptors potently activate JNK (SAPK). Evidence for a divergence from the tyrosine kinase signaling pathway. J Biol Chem. 1995 Mar 10;270(10):5620–5624. doi: 10.1074/jbc.270.10.5620. [DOI] [PubMed] [Google Scholar]
  8. Cuenda A., Rouse J., Doza Y. N., Meier R., Cohen P., Gallagher T. F., Young P. R., Lee J. C. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett. 1995 May 8;364(2):229–233. doi: 10.1016/0014-5793(95)00357-f. [DOI] [PubMed] [Google Scholar]
  9. Dalton S., Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. doi: 10.1016/0092-8674(92)90194-h. [DOI] [PubMed] [Google Scholar]
  10. Dudley D. T., Pang L., Decker S. J., Bridges A. J., Saltiel A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. doi: 10.1073/pnas.92.17.7686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. 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. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  12. Dérijard B., Raingeaud J., Barrett T., Wu I. H., Han J., Ulevitch R. J., Davis R. J. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. doi: 10.1126/science.7839144. [DOI] [PubMed] [Google Scholar]
  13. Galcheva-Gargova Z., Dérijard B., Wu I. H., Davis R. J. An osmosensing signal transduction pathway in mammalian cells. Science. 1994 Aug 5;265(5173):806–808. doi: 10.1126/science.8047888. [DOI] [PubMed] [Google Scholar]
  14. Gille H., Kortenjann M., Thomae O., Moomaw C., Slaughter C., Cobb M. H., Shaw P. E. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J. 1995 Mar 1;14(5):951–962. doi: 10.1002/j.1460-2075.1995.tb07076.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gille H., Sharrocks A. D., Shaw P. E. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature. 1992 Jul 30;358(6385):414–417. doi: 10.1038/358414a0. [DOI] [PubMed] [Google Scholar]
  16. Gille H., Strahl T., Shaw P. E. Activation of ternary complex factor Elk-1 by stress-activated protein kinases. Curr Biol. 1995 Oct 1;5(10):1191–1200. doi: 10.1016/s0960-9822(95)00235-1. [DOI] [PubMed] [Google Scholar]
  17. Ginty D. D., Bonni A., Greenberg M. E. Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell. 1994 Jun 3;77(5):713–725. doi: 10.1016/0092-8674(94)90055-8. [DOI] [PubMed] [Google Scholar]
  18. Graham R., Gilman M. Distinct protein targets for signals acting at the c-fos serum response element. Science. 1991 Jan 11;251(4990):189–192. doi: 10.1126/science.1898992. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Han J., Lee J. D., Bibbs L., Ulevitch R. J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994 Aug 5;265(5173):808–811. doi: 10.1126/science.7914033. [DOI] [PubMed] [Google Scholar]
  21. Herrera R. E., Shaw P. E., 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. doi: 10.1038/340068a0. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Hill C. S., 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. doi: 10.1016/0092-8674(93)90238-l. [DOI] [PubMed] [Google Scholar]
  24. Hill C. S., Treisman R. Differential activation of c-fos promoter elements by serum, lysophosphatidic acid, G proteins and polypeptide growth factors. EMBO J. 1995 Oct 16;14(20):5037–5047. doi: 10.1002/j.1460-2075.1995.tb00186.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hill C. S., Wynne J., Treisman R. Serum-regulated transcription by serum response factor (SRF): a novel role for the DNA binding domain. EMBO J. 1994 Nov 15;13(22):5421–5432. doi: 10.1002/j.1460-2075.1994.tb06877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Howe L. R., Leevers S. J., Gómez N., Nakielny S., Cohen P., Marshall C. J. Activation of the MAP kinase pathway by the protein kinase raf. Cell. 1992 Oct 16;71(2):335–342. doi: 10.1016/0092-8674(92)90361-f. [DOI] [PubMed] [Google Scholar]
  27. Janknecht R., Ernst W. H., Nordheim A. SAP1a is a nuclear target of signaling cascades involving ERKs. Oncogene. 1995 Mar 16;10(6):1209–1216. [PubMed] [Google Scholar]
  28. Janknecht R., Ernst W. H., Pingoud V., Nordheim A. Activation of ternary complex factor Elk-1 by MAP kinases. EMBO J. 1993 Dec 15;12(13):5097–5104. doi: 10.1002/j.1460-2075.1993.tb06204.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jiang Y., Chen C., Li Z., Guo W., Gegner J. A., Lin S., Han J. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996 Jul 26;271(30):17920–17926. doi: 10.1074/jbc.271.30.17920. [DOI] [PubMed] [Google Scholar]
  30. Kortenjann M., Thomae O., Shaw P. E. Inhibition of v-raf-dependent c-fos expression and transformation by a kinase-defective mutant of the mitogen-activated protein kinase Erk2. Mol Cell Biol. 1994 Jul;14(7):4815–4824. doi: 10.1128/mcb.14.7.4815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kyriakis J. M., Banerjee P., Nikolakaki E., Dai T., Rubie E. A., Ahmad M. F., Avruch J., Woodgett J. R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. doi: 10.1038/369156a0. [DOI] [PubMed] [Google Scholar]
  32. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  33. Lee J. C., Laydon J. T., McDonnell P. C., Gallagher T. F., Kumar S., Green D., McNulty D., Blumenthal M. J., Heys J. R., Landvatter S. W. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994 Dec 22;372(6508):739–746. doi: 10.1038/372739a0. [DOI] [PubMed] [Google Scholar]
  34. Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
  35. Livingstone C., Patel G., Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995 Apr 18;14(8):1785–1797. doi: 10.1002/j.1460-2075.1995.tb07167.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  37. Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., 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. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
  38. Norman C., Runswick M., Pollock R., Treisman R. Isolation and properties of cDNA clones encoding SRF, a transcription factor that binds to the c-fos serum response element. Cell. 1988 Dec 23;55(6):989–1003. doi: 10.1016/0092-8674(88)90244-9. [DOI] [PubMed] [Google Scholar]
  39. Price M. A., Rogers A. E., 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. doi: 10.1002/j.1460-2075.1995.tb07257.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Radler-Pohl A., Sachsenmaier C., Gebel S., Auer H. P., Bruder J. T., Rapp U., Angel P., Rahmsdorf H. J., Herrlich P. UV-induced activation of AP-1 involves obligatory extranuclear steps including Raf-1 kinase. EMBO J. 1993 Mar;12(3):1005–1012. doi: 10.1002/j.1460-2075.1993.tb05741.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Raingeaud J., Whitmarsh A. J., Barrett T., Dérijard B., Davis R. J. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247–1255. doi: 10.1128/mcb.16.3.1247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rouse J., Cohen P., Trigon S., Morange M., Alonso-Llamazares A., Zamanillo D., Hunt T., Nebreda A. R. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994 Sep 23;78(6):1027–1037. doi: 10.1016/0092-8674(94)90277-1. [DOI] [PubMed] [Google Scholar]
  43. Shaw P. E., Schröter H., Nordheim A. The ability of a ternary complex to form over the serum response element correlates with serum inducibility of the human c-fos promoter. Cell. 1989 Feb 24;56(4):563–572. doi: 10.1016/0092-8674(89)90579-5. [DOI] [PubMed] [Google Scholar]
  44. Stokoe D., Campbell D. G., Nakielny S., Hidaka H., Leevers S. J., Marshall C., Cohen P. MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J. 1992 Nov;11(11):3985–3994. doi: 10.1002/j.1460-2075.1992.tb05492.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Subramaniam M., Schmidt L. J., Crutchfield C. E., 3rd, Getz M. J. Negative regulation of serum-responsive enhancer elements. Nature. 1989 Jul 6;340(6228):64–66. doi: 10.1038/340064a0. [DOI] [PubMed] [Google Scholar]
  46. Sánchez I., Hughes R. T., Mayer B. J., Yee K., Woodgett J. R., Avruch J., Kyriakis J. M., Zon L. I. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. doi: 10.1038/372794a0. [DOI] [PubMed] [Google Scholar]
  47. Tan Y., Rouse J., Zhang A., Cariati S., Cohen P., Comb M. J. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 1996 Sep 2;15(17):4629–4642. [PMC free article] [PubMed] [Google Scholar]
  48. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]
  49. Treisman R. The SRE: a growth factor responsive transcriptional regulator. Semin Cancer Biol. 1990 Feb;1(1):47–58. [PubMed] [Google Scholar]
  50. Treisman R. Transient accumulation of c-fos RNA following serum stimulation requires a conserved 5' element and c-fos 3' sequences. Cell. 1985 Oct;42(3):889–902. doi: 10.1016/0092-8674(85)90285-5. [DOI] [PubMed] [Google Scholar]
  51. Waskiewicz A. J., Cooper J. A. Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr Opin Cell Biol. 1995 Dec;7(6):798–805. doi: 10.1016/0955-0674(95)80063-8. [DOI] [PubMed] [Google Scholar]
  52. Whitmarsh A. J., Shore P., Sharrocks A. D., Davis R. J. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. doi: 10.1126/science.7618106. [DOI] [PubMed] [Google Scholar]
  53. Wilson T., Treisman R. Fos C-terminal mutations block down-regulation of c-fos transcription following serum stimulation. EMBO J. 1988 Dec 20;7(13):4193–4202. doi: 10.1002/j.1460-2075.1988.tb03316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yan M., Dai T., Deak J. C., Kyriakis J. M., Zon L. I., Woodgett J. R., Templeton D. J. Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature. 1994 Dec 22;372(6508):798–800. doi: 10.1038/372798a0. [DOI] [PubMed] [Google Scholar]
  55. Zinck R., Cahill M. A., Kracht M., Sachsenmaier C., Hipskind R. A., Nordheim A. Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1. Mol Cell Biol. 1995 Sep;15(9):4930–4938. doi: 10.1128/mcb.15.9.4930. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES