Regulation Of Leukotriene C4 Synthase Gene Expression By Sp1 And Sp3 In Mononuclear Phagocytes

  • Kenneth J. Serio
  • Craig R. Hodulik
  • Timothy D. Bigby
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 507)


A large body of experimental evidence has implicated the cysteinyl leukotrienes in a variety of inflammatory responses201C;2. Leukotriene C4 (LTC4) synthase (Mr of 16,568; EC# is a selective, membrane-bound glutathione-S-transferase that catalyzes the conversion of LTA4 to LTC4. Although LTC4 synthase enzymatic activity is found in various cell types, mRNA for LTC4 synthase is present only in eosinophils, basophils, mast cells, and cells of monocyte/macrophage lineage. Previous studies suggest that LTC4 synthase expression is increased in the bronchial mucosa of patients with aspirin-sensitive asthma3. The gene for LTC4 synthase has been cloned, sequenced, and mapped to the distal region of chromosome 545. The LTC4 synthase 5’ flanking region lacks a TATA box but has known consensus sites for ets, AP-1, AP-2, and Sp145. Previous work from our laboratory indicates that LTC4 synthase gene expression is upregulated by transforming growth factor-ß (TGF-ß) through a transcriptional mechanism in the monocyte-like cell line, THP-16. The purpose of this study was to begin to investigate the molecular mechanisms of regulation of transcription of the LTC4 synthase gene in mononuclear phagocytes.


HeLa Cell Electrophoretic Mobility Shift Assay Reporter Activity Consensus Site HeLa Nuclear Extract 
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  1. 1.
    Lewis, R.A., K.F. Austen, and R.J. Soberman, Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases, N. Engl. J. Med. 323: 645–655 (1990).PubMedCrossRefGoogle Scholar
  2. 2.
    Namovic, M.T., R.E. Walsh, C. Goodfellow, R.R. Harris, G.W. Carter, and R.L. Bell, Pharmacological modulation of eosinophil influx into the lungs of Brown Norway rats, Eur. J. of Pharmacol. 315: 81–88 (1996).CrossRefGoogle Scholar
  3. 3.
    Cowburn, A.S., K. Sladek, J. Soja, L. Adamek, E. Nizankowska, A. Szczeklik, B.K. Lam, J.F. Penrose, K.F. Austen, S.T. Holgate, and A.P. Sampson, Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma, J. Clin. Invest. 101: 834–846 (1997).CrossRefGoogle Scholar
  4. 4.
    Bigby, T.D., C.R. Hodulik, K.C. Arden, and L. Fu., Molecular cloning of the human leukotriene C4 synthase gene and assignment to chromosome 5q35, Mol. Med. 2: 637–646 (1996).PubMedCentralPubMedGoogle Scholar
  5. 5.
    Penrose, J.F., J. Spector, M. Baldasaro, K. Xu, J. Boyce, J.P. Arm, K.F. Austen, and B.K. Lam, Molecular cloning of the gene for human leukotriene C4 synthase. Organization, nucleotide sequence, and chromosomal localization to 5g35, J. Biol. Chem. 271: 11356–11361 (1996).PubMedCrossRefGoogle Scholar
  6. 6.
    Riddick, C.A., K.J. Serio, C.R. Hodulik, W.L. Ring, M.S. Regan, and T.D. Bigby, TGF-13 increases leukotriene C4 synthase expression in the monocyte-like cell line, THP-1, J. Immunol. 162: 1102–1107 (1999).Google Scholar
  7. 7.
    Hagen, G., S. Muller, M. Beato, and G. Suske, Cloning by recognition site screening of two novel GT box binding proteins: a family of Spl related genes, Nucl. Acids Res. 20: 5519–5525 (1992).CrossRefGoogle Scholar
  8. 8.
    Kingsley, C. and A. Winoto, Cloning of GT binding proteins: a novel Spl multigene family regulating T-cell receptor gene expression, Mol. Cell Biol. 12: 4251–4261 (1992).Google Scholar
  9. 9.
    Kadonaga, J.T., K.R. Carter, F.R. Marsiarz, and R. Tjian, Isolation of cDNA encoding transcription factor Spl and functional analysis of the DNA binding domain, Cell 51: 1079–1090 (1987).PubMedCrossRefGoogle Scholar
  10. 10.
    Hoey, T., R.O.J. Weinzierl, G. Gill, J.-L. Chen, B.D. Dynlacht, and R. Tjian, Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators, Cell 72: 247–260 (1993).PubMedCrossRefGoogle Scholar
  11. 11.
    Majello, B., P. De Luca, and L. Lania, Sp3 is a bifunctional regulator with modular independent activation and repression domains, J. Biol. Chem. 272: 4021–4026 (1997).PubMedCrossRefGoogle Scholar
  12. 12.
    Hauses, M., R.R. Tonjes, and M. Grez, The transcription factor Sp1 regulates the myeloid-specific expression of the human hematopoietic cell kinase (HCK) gene through binding to two adjacent GC boxes within the HCK promoter-proximal region, J. Biol. Chem. 273: 31844–31852 (1998).PubMedCrossRefGoogle Scholar
  13. 13.
    Shou, Y., S. Baron, and M. Ponce, An Spl -binding silencer element is a critical negative regulator of the megakaryocyte-specific a1Ib gene, J. Biol. Chem. 273: 5716–5726 (1998).PubMedCrossRefGoogle Scholar
  14. 14.
    Black, A.R., D. Jensen, S. Lin, and J.C. Azizkhan, Growth/cell cycle regulation of Spl phosphorylation, J. Biol. Chem 274: 1207–1215 (1999).PubMedCrossRefGoogle Scholar
  15. 15.
    Han, I. and J.E. Kudlow, Reduced O glycosylation of Spl is associated with increased proteasome susceptibility, Mol. Cell. Biol. 17: 2550–2558 (1997).Google Scholar
  16. 16.
    Zhang, D.E., C.J. Hetherington, S. Tan, S.E. Dziennis, D.A. Gonzalez, H.M. Chen, and D.G. Tenen, Sp1 is a critical factor for the monocytic specific expression of human CD14, J. Biol. Chem. 269: 11425–11434 (1994).PubMedGoogle Scholar
  17. 17.
    Ebert, S.N. and D.L. Wong, Differential Activation of the Rat Phenylethanolamine N-Methyltransferase Gene by Spl and Egr-1, J. Biol. Chem. 270: 17299–17305 (1995).PubMedCrossRefGoogle Scholar
  18. 18.
    Hagen, G., J. Dennig, A. Preiss, M. Beato, and G. Suske, Functional analyses of the transcription factor Sp4 properties distinct from Spl and Sp3, J. Biol. Chem. 270: 24989–24994 (1995).PubMedCrossRefGoogle Scholar
  19. 19.
    Li, R., Z. Hodny, K. Luciakova, P. Barath, and B.D. Nelson, Spl Activates and Inhibits Transcription from Separate Elements in the Proximal Promoter of the Human Adenine Nucleotide Translocase 2 (ANT2) Gene, J. Biol. Chem. 271: 18925–18930 (1996).PubMedCrossRefGoogle Scholar
  20. 20.
    Majello, B., P. De Luca, G. Hagen, G. Suske, and L. Lania, Different members of the Spl multigene family exert opposite transcriptional regulation of the long-terminal repeat of HIV-1, Nucl. Acids Res. 22: 4914–4921 (1994).CrossRefGoogle Scholar
  21. 21.
    Rajakumar, R. A., S. Thamotharan, R.K. Menon, and S.U. Devaskar, Spl and Sp3 regulate transcriptional activity of the facilitative glucose transporter isoform-3 gene in mammalian neuroblast and trophoblasts, J. Biol Chem 273(42), 27474–27483 (1998).PubMedCrossRefGoogle Scholar
  22. 22.
    Bigger, C.B., I.N. Melnikova, and P.D. Gardner, Spl and Sp3 regulate expression of the neuronal nicotinic acetycholine receptor 134 subunit gene, J. Biol. Chem. 272: 25976–25982 (1997).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Kenneth J. Serio
    • 1
  • Craig R. Hodulik
    • 1
  • Timothy D. Bigby
    • 1
  1. 1.Department of Veteran Affairs Medical Center, San Diego and the Department of MedicineUniversity of California, San DiegoSan Diego

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