Abstract
The clinical success of zileuton and other 5-lipoxygenase (5-LO) inhibitors for the treatment of asthma strongly supports the hypothesis that alterations in the expression of 5-LO have important implications in the pathogenesis of diseases characterized by excess leukotriene production. In a clinical trial with zileuton about 50% of patients have shown a sustained improvement in FEV1 (force expiratory volume at 1 sec) of ≥ 10% in response to 5-LO inhibition [1]. It is likely that the issues of incomplete therapeutic responses in asthma are not isolated to 5-LO inhibitors perse, but are problems associated with all antiasthmatic drugs, and reflect the fact that asthma is a heterogeneous disease with complex and interdependent genetic and environmental etiologic factors [2, 3]. One intriguing possibility is that the leukocytes of asthmatics differ in their functional expression of 5-LO, such that 5-LO products contribute to a variable extent in the overall pathogenesis of asthma. As a result of these differences, patients overexpressing 5-LO, and therefore 5-LO products, will be more responsive to 5-LO inhibition, whereas other patients whose disease is less dependent on 5-LO activity will be less responsive to these drugs. Is there a potential for genetic differences in the 5-LO gene to be responsible for altered 5-LO expression and some of the observed heterogeneity among asthmatic patients? The answer to this question appears to be yes, and because of its essential role in the formation of leukotrienes, 5-LO is considered to be an excellent candidate gene in the ongoing search for genetic polymorphisms that may account for asthma development or phenotypic variability. This chapter will review what is known about 5-LO gene regulation and how this regulation may be altered by naturally occurring promoter mutations.
Keywords
- Electrophoretic Mobility Shift Assay
- Promoter Mutation
- Consensus Binding Site
- Simple Sequence Length Polymorphism
- Prostaglandin Leukot Essent Fatty Acid
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
DuBuske LM, Grossman J, Dube L, Swanson L, Lancaster J, The Zileuton Study Group (1997) Random trial of zileuton in patients with moderate asthma: Effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Am J Managed Care 3: 633–640
Sheffer AL, Taggart VS (1993) The National Asthma Education Program Expert panel report guidelines for the diagnosis and management of asthma. Med Care 31: MS20
Holgate S (1993) Mediator and cytokine mechanisms in asthma. Thorax 48: 103
Samuelsson B, Rouzer CA, Matsumoto T (1987) Human leukocyte 5-lipoxygenase: an enzyme possessing dual enzymatic activities and a multicomponent regulatory system Advances Prostaglandin Thromboxane Leukot Res 17A: 1–11
Samuelsson B, Funk CD (1989) Enzymes involved in the biosynthesis of leukotriene B4. J Biol Chem 264: 19469–19472
Hammarberg T, Zhang Y Y, Lind B, Radmark O, Samuelsson B (1995) Mutations at the C-terminal isoleucine and other potential iron ligands of 5-lipoxygenase. Eur J Biochem 230: 401–407
Dixon RA, Jones RE, Diehl RE, Bennett CD, Kargman S, Rouzer CA (1988) Cloning of the cDNA for human 5-lipoxygenase. Proc Nat Acad Sci USA 85: 416–420
Matsumoto T, Funk CD, Radmark O, Hoog JO, Jornvall H, Samuelsson B (1988) Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci USA 85: 26–30
Funk CD, Hoshiko S, Matsumoto T, Radmark O, Samuelsson B (1989) Characterization of the human 5-lipoxygenase gene. Proc Nat Acad Sci 86: 2587–2591
Hoshiko S, Radmark O, Samuelsson B (1990) Characterization of the human 5-lipoxygenase gene promoter. Proc Nat Acad Sci USA 87: 9073–9077
Stene DO, Murphy RC (1988) Metabolism of leukotriene E4 in isolated rat hepatocytes: Identification of beta-oxidation products of sulfidopeptide leukotrienes. J Biol Chem 263: 2773–2778
Sala A, Voelkel N, Maclouf J, Murphy RC (1990) Lcukotriene E4 elimination and metabolism in normal human subjects. J Biol Chem 265: 21771–21778
Murakami M, Austen KF, Bingham CO III, Friend DS, Penrose JF, Arm JP (1995) Interleukin-3 regulates development of the 5-lipoxygenase/leukotriene C4 synthase pathway in mouse mast cells. J Biol Chem 270: 22653–22656
Samuelsson B (1983) Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 237: 1171–1176
Bergstrom S (1967) Prostaglandins: members of a hormonal system These physiologically very potent compounds of a ubiquitous occurrence are formed from essential fatty acids. Science 270: 1773–1774
Rosenthal MD, Rzigalinski BA, Blackmore PF, Franson RC (1995) Cellular regulation of arachidonate mobilization and metabolism. Prostaglandins Leukot Essent Fatty Acids 52: 93–98
Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, Gillard JW, Miller DK (1990) Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature 343: 282–284
Reid GK, Kargman S, Vickers PJ, Mancini JA, Leveille C, Ethier D, Miller DK, Gillard JW, Dixon RA, Evans JF (1990) Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis. J Biol Chem 265: 19818–19823
Coffey M, Peters-Golden M, Fantone JCD, Sporn PH (1992) Membrane association of active 5-lipoxygenase in resting cells Evidence for novel regulation of the enzyme in the rat alveolar macrophage. J Biol Chem 267: 570–576
Lepley RA, Fitzpatrick FA (1996) Inhibition of mitogen-activated protein kinase kinase blocks activation and redistribution of 5-lipoxygenase in HL-60 cells. Arch Biochem Biophys 331: 141–144
Lepley RA, Fitzpatrick FA (1994) Irreversible inactivation of 5-lipoxygenase by leukotriene A4 Characterization of product inactivation with purified enzyme and intact leukocytes. J Biol Chem 269: 2627–2631
Ring WL, Riddick CA, Baker JR, Munafo DA, Bigby TD (1996) Lymphocytes stimulate expression of 5-lipoxygenase and its activating protein in monocytes in vitro via granulocyte macrophage colony-stimulating factor and interleukin 3. J Clin Invest 97: 1293–1301
Steinhilber D (1994) 5-Lipoxygenase: enzyme expression and regulation of activity. Pharmaceutica Acta Helvetiae 69: 3–14
Steinhilber D, Brungs M, Radmark O, Samuelsson B (1995) Transforming growth factor-beta and 1,25-dihydroxyvitamin D3 induce 5-lipoxygenase activity during myeloid cell maturation. Advances Prostaglandin Thromboxane Leukot Res 23: 449–451
Ponton A, Thirion JP, Sirois P (1996) Changes in chromatin conformation regulate the 5-lipoxygenase gene expression during differentiation of HL60 cells. Prostaglandins Leukot Essent Fatty Acids 55: 139–143
Stankova J, Rola-Pleszczynski M, Dubois C M (1995) Granulocyte-macrophage colony-stimulating factor increases 5-lipoxygenase gene transcription and protein expression in human neutrophils. Blood 85: 3719–3726
In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP et al (1997) Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 99: 1130–1137
Silverman ES, Du J, DeSanctis GT, Radmark O, Samuelsson B, Drazen JM, Collins T (1998) Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am J Cell Mol Bio 19: 316–323
Ponton A, Thirion J P, Sirois P (1997) Repression of the 5-lipoxygenase gene by c-myb overexpression in differentiated HL-60 cells. Prostaglandins 53: 49–58
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5: 874–879
Khachigian LM, Linder V, Williams AJ, Collins T (1996) Egr-1-Induced endothelial gene expression: a common theme in vascular injury. Science 271: 1427–1431
Weber JL, May PE (1989) Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44: 388–396
Buratowski S (1995) Mechanisms of gene activation. Science 270: 1773–1774
Janknecht R, Hunter T (1996) A growing coactivator network. Nature 383: 22–23
Hagen G, Muller S, Beato M, Suske G (1994) Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes. Nucleic Acids Res 20: 5519–5525
Courey A J, Tjian R (1992) Mechanisms of transcriptional control as revealed by studies of human transcription factor Spl. In: Transcriptional regulation, Vol 28. Cold Spring Harbor Press, Cold Spring Harbor, 743–769
Gashler A, Sukhatme VP (1995) Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol 50: 191–224
Silverman ES, Khachigian LM, Lindner V, Williams AJ, Collins T (1997) Inducible PDGF A-chain transcription in smooth muscle cells is mediated by Egr-1 displacement of Sp1 and Sp3. Am J Physiol 273: H1415–H1426
Khachigian LM, Williams AJ, Collins T (1995) Interplay of SO and Egr-1 in the proximal platelet-derived growth factor A-chain promoter in cultured vascular endothelial cells. J Biol Chem 270: 27679–27686
Cui MZ, Graham CNP, Oeth P, Lason H, Smith M, Huang RP, Adamson ED, Mackman N (1995) Transcriptional Regulation of the tissue factor gene in human epithelial cells is mediated by Sp1 and Egr-1. J Biol Chem 271: 2731–2739
Khachigian L, Collins T (1997) Transcriptional activation in vascular endothelium involving Egr-1. Circ Res 81: 1–4
Kharabanda S, Nakamura T, Stone R, Hass R, Bernstein S, Datta R, Sukhatme VP, Kufe D (1991) Expression of the early growth response 1 and 2 zinc-finger genes during induction of monocytic differentiation. J Clin Invest 88: 571–577
Dent CL, Latchman DS (1993) In: DS Latchman (eds): Transcription factors: A practical approach. Oxford University Press, Oxford, 1–26
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Basel AG
About this chapter
Cite this chapter
Silverman, E.S., In, K.H., Collins, T., Drazen, J.M. (1999). Genetic polymorphisms of 5-LO. In: Folco, G., Samuelsson, B., Murphy, R.C. (eds) Novel Inhibitors of Leukotrienes. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8703-8_10
Download citation
DOI: https://doi.org/10.1007/978-3-0348-8703-8_10
Publisher Name: Birkhäuser, Basel
Print ISBN: 978-3-0348-9736-5
Online ISBN: 978-3-0348-8703-8
eBook Packages: Springer Book Archive