Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Jun;16(6):2913–2921. doi: 10.1128/mcb.16.6.2913

Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene.

R J Grumont 1, J E Rasko 1, A Strasser 1, S Gerondakis 1
PMCID: PMC231285  PMID: 8649402

Abstract

PAC-1, an early-response gene originally identified in activated T cells, encodes a dual-specificity mitogen-activated protein kinase phosphatase. Here we report on the regulation of PAC-1 expression in murine hemopoietic cells. PAC-1 mRNA levels rapidly increase in mitogen-stimulated lymphocytes, with the induced expression being transient in B cells but sustained in activated T cells. Transfection analysis of murine PAC-1 promoter-reporter constructs established that in T cells, sequences necessary for basal and induced transcription reside within a 200-bp region located immediately upstream of the transcription initiation sites. Basal transcription is regulated in part by an E-box element that binds a 53-kDa protein. PAC-1 transcription induced by phorbol myristate acetate stimulation and the expression of the v-ras or v-raf oncogene is mediated via the E-box motif and an AP-2-related site and coincides with increased binding activity of the constitutive 53-kDa E-box-binding protein and induced binding of AP-2. The ability of an interfering ERK-2 mutant to block phorbol myristate acetate and v-ras-dependent PAC-1 transcription indicates that mitogen-activated protein kinase activation is necessary for these stimuli to induce transcription of the PAC-1 gene in T cells.

Full Text

The Full Text of this article is available as a PDF (809.3 KB).

Selected References

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

  1. Alessi D. R., Gomez N., Moorhead G., Lewis T., Keyse S. M., Cohen P. Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines. Curr Biol. 1995 Mar 1;5(3):283–295. doi: 10.1016/s0960-9822(95)00059-5. [DOI] [PubMed] [Google Scholar]
  2. Alessi D. R., Smythe C., Keyse S. M. The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. Oncogene. 1993 Jul;8(7):2015–2020. [PubMed] [Google Scholar]
  3. Avruch J., Zhang X. F., Kyriakis J. M. Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci. 1994 Jul;19(7):279–283. doi: 10.1016/0968-0004(94)90005-1. [DOI] [PubMed] [Google Scholar]
  4. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. doi: 10.1073/pnas.90.13.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Charles C. H., Abler A. S., Lau L. F. cDNA sequence of a growth factor-inducible immediate early gene and characterization of its encoded protein. Oncogene. 1992 Jan;7(1):187–190. [PubMed] [Google Scholar]
  6. Chen R. H., Sarnecki C., Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992 Mar;12(3):915–927. doi: 10.1128/mcb.12.3.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cobb M. H., Hepler J. E., Cheng M., Robbins D. The mitogen-activated protein kinases, ERK1 and ERK2. Semin Cancer Biol. 1994 Aug;5(4):261–268. [PubMed] [Google Scholar]
  8. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  9. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  10. Denu J. M., Dixon J. E. A catalytic mechanism for the dual-specific phosphatases. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):5910–5914. doi: 10.1073/pnas.92.13.5910. [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. Gerondakis S., Economou C., Grumont R. J. Structure of the gene encoding the murine dual specificity tyrosine-threonine phosphatase PAC1. Genomics. 1994 Nov 1;24(1):182–184. doi: 10.1006/geno.1994.1598. [DOI] [PubMed] [Google Scholar]
  13. Grumont R. J., Gerondakis S. Murine c-rel transcription is rapidly induced in T-cells and fibroblasts by mitogenic agents and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Cell Growth Differ. 1990 Aug;1(8):345–350. [PubMed] [Google Scholar]
  14. Grumont R. J., Gerondakis S. The subunit composition of NF-kappa B complexes changes during B-cell development. Cell Growth Differ. 1994 Dec;5(12):1321–1331. [PubMed] [Google Scholar]
  15. Grumont R. J., Richardson I. B., Gaff C., Gerondakis S. rel/NF-kappa B nuclear complexes that bind kB sites in the murine c-rel promoter are required for constitutive c-rel transcription in B-cells. Cell Growth Differ. 1993 Sep;4(9):731–743. [PubMed] [Google Scholar]
  16. Guan K. L., Broyles S. S., Dixon J. E. A Tyr/Ser protein phosphatase encoded by vaccinia virus. Nature. 1991 Mar 28;350(6316):359–362. doi: 10.1038/350359a0. [DOI] [PubMed] [Google Scholar]
  17. Guan K. L., Butch E. Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J Biol Chem. 1995 Mar 31;270(13):7197–7203. doi: 10.1074/jbc.270.13.7197. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
  20. Hipskind R. A., Büscher D., Nordheim A., Baccarini M. Ras/MAP kinase-dependent and -independent signaling pathways target distinct ternary complex factors. Genes Dev. 1994 Aug 1;8(15):1803–1816. doi: 10.1101/gad.8.15.1803. [DOI] [PubMed] [Google Scholar]
  21. Ho S. N., Hunt H. D., Horton R. M., Pullen J. K., Pease L. R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. doi: 10.1016/0378-1119(89)90358-2. [DOI] [PubMed] [Google Scholar]
  22. Imagawa M., Chiu R., Karin M. Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. Cell. 1987 Oct 23;51(2):251–260. doi: 10.1016/0092-8674(87)90152-8. [DOI] [PubMed] [Google Scholar]
  23. Ishibashi T., Bottaro D. P., Michieli P., Kelley C. A., Aaronson S. A. A novel dual specificity phosphatase induced by serum stimulation and heat shock. J Biol Chem. 1994 Nov 25;269(47):29897–29902. [PubMed] [Google Scholar]
  24. Johnson G. L., Vaillancourt R. R. Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol. 1994 Apr;6(2):230–238. doi: 10.1016/0955-0674(94)90141-4. [DOI] [PubMed] [Google Scholar]
  25. Kannan P., Buettner R., Chiao P. J., Yim S. O., Sarkiss M., Tainsky M. A. N-ras oncogene causes AP-2 transcriptional self-interference, which leads to transformation. Genes Dev. 1994 Jun 1;8(11):1258–1269. doi: 10.1101/gad.8.11.1258. [DOI] [PubMed] [Google Scholar]
  26. Kelly K., Davis P., Mitsuya H., Irving S., Wright J., Grassmann R., Fleckenstein B., Wano Y., Greene W., Siebenlist U. A high proportion of early response genes are constitutively activated in T cells by HTLV-I. Oncogene. 1992 Aug;7(8):1463–1470. [PubMed] [Google Scholar]
  27. Keyse S. M., Emslie E. A. Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature. 1992 Oct 15;359(6396):644–647. doi: 10.1038/359644a0. [DOI] [PubMed] [Google Scholar]
  28. Kwak S. P., Dixon J. E. Multiple dual specificity protein tyrosine phosphatases are expressed and regulated differentially in liver cell lines. J Biol Chem. 1995 Jan 20;270(3):1156–1160. doi: 10.1074/jbc.270.3.1156. [DOI] [PubMed] [Google Scholar]
  29. Köntgen F., Grumont R. J., Strasser A., Metcalf D., Li R., Tarlinton D., Gerondakis S. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 1995 Aug 15;9(16):1965–1977. doi: 10.1101/gad.9.16.1965. [DOI] [PubMed] [Google Scholar]
  30. Lane P., Brocker T., Hubele S., Padovan E., Lanzavecchia A., McConnell F. Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation. J Exp Med. 1993 Apr 1;177(4):1209–1213. doi: 10.1084/jem.177.4.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lüscher B., Mitchell P. J., Williams T., Tjian R. Regulation of transcription factor AP-2 by the morphogen retinoic acid and by second messengers. Genes Dev. 1989 Oct;3(10):1507–1517. doi: 10.1101/gad.3.10.1507. [DOI] [PubMed] [Google Scholar]
  33. Marshall C. J. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994 Feb;4(1):82–89. doi: 10.1016/0959-437x(94)90095-7. [DOI] [PubMed] [Google Scholar]
  34. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  35. Martin M., Strasser A., Baumgarth N., Cicuttini F. M., Welch K., Salvaris E., Boyd A. W. A novel cellular model (SPGM 1) of switching between the pre-B cell and myelomonocytic lineages. J Immunol. 1993 May 15;150(10):4395–4406. [PubMed] [Google Scholar]
  36. McCarthy S. A., Samuels M. L., Pritchard C. A., Abraham J. A., McMahon M. Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes Dev. 1995 Aug 15;9(16):1953–1964. doi: 10.1101/gad.9.16.1953. [DOI] [PubMed] [Google Scholar]
  37. Misra-Press A., Rim C. S., Yao H., Roberson M. S., Stork P. J. A novel mitogen-activated protein kinase phosphatase. Structure, expression, and regulation. J Biol Chem. 1995 Jun 16;270(24):14587–14596. doi: 10.1074/jbc.270.24.14587. [DOI] [PubMed] [Google Scholar]
  38. Mitchell P. J., Wang C., Tjian R. Positive and negative regulation of transcription in vitro: enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell. 1987 Sep 11;50(6):847–861. doi: 10.1016/0092-8674(87)90512-5. [DOI] [PubMed] [Google Scholar]
  39. Nebreda A. R. Inactivation of MAP kinases. Trends Biochem Sci. 1994 Jan;19(1):1–2. doi: 10.1016/0968-0004(94)90163-5. [DOI] [PubMed] [Google Scholar]
  40. Nishida E., Gotoh Y. The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem Sci. 1993 Apr;18(4):128–131. doi: 10.1016/0968-0004(93)90019-j. [DOI] [PubMed] [Google Scholar]
  41. Noguchi T., Metz R., Chen L., Mattéi M. G., Carrasco D., Bravo R. Structure, mapping, and expression of erp, a growth factor-inducible gene encoding a nontransmembrane protein tyrosine phosphatase, and effect of ERP on cell growth. Mol Cell Biol. 1993 Sep;13(9):5195–5205. doi: 10.1128/mcb.13.9.5195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Nur-E-Kamal M. S., Sizeland A., D'Abaco G., Maruta H. Asparagine 26, glutamic acid 31, valine 45, and tyrosine 64 of Ras proteins are required for their oncogenicity. J Biol Chem. 1992 Jan 25;267(3):1415–1418. [PubMed] [Google Scholar]
  43. Peraldi P., Zhao Z., Filloux C., Fischer E. H., Van Obberghen E. Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5002–5006. doi: 10.1073/pnas.91.11.5002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. 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]
  45. Robbins D. J., Zhen E., Cheng M., Xu S., Ebert D., Cobb M. H. MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network. Adv Cancer Res. 1994;63:93–116. doi: 10.1016/s0065-230x(08)60399-1. [DOI] [PubMed] [Google Scholar]
  46. Rodriguez-Viciana P., Warne P. H., Dhand R., Vanhaesebroeck B., Gout I., Fry M. J., Waterfield M. D., Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527–532. doi: 10.1038/370527a0. [DOI] [PubMed] [Google Scholar]
  47. Rohan P. J., Davis P., Moskaluk C. A., Kearns M., Krutzsch H., Siebenlist U., Kelly K. PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Science. 1993 Mar 19;259(5102):1763–1766. doi: 10.1126/science.7681221. [DOI] [PubMed] [Google Scholar]
  48. Sun H., Charles C. H., Lau L. F., Tonks N. K. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993 Nov 5;75(3):487–493. doi: 10.1016/0092-8674(93)90383-2. [DOI] [PubMed] [Google Scholar]
  49. Tanigawa T., Nicola N., McArthur G. A., Strasser A., Begley C. G. Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor. Blood. 1995 Jan 15;85(2):379–390. [PubMed] [Google Scholar]
  50. 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]
  51. Wang Y., Larsen A. S., Peterlin B. M. A tissue-specific transcriptional enhancer is found in the body of the HLA-DR alpha gene. J Exp Med. 1987 Sep 1;166(3):625–636. doi: 10.1084/jem.166.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ward Y., Gupta S., Jensen P., Wartmann M., Davis R. J., Kelly K. Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Nature. 1994 Feb 17;367(6464):651–654. doi: 10.1038/367651a0. [DOI] [PubMed] [Google Scholar]
  53. Williams T., Tjian R. Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev. 1991 Apr;5(4):670–682. doi: 10.1101/gad.5.4.670. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES