Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Sep 1, 1992; 89(17): 8215–8219.

Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter.


The human neutrophil and monocyte-derived serine protease homologues neutrophil elastase (NE), proteinase 3 (PR3), and azurocidin (AZU) are involved in a variety of immune defense reactions. NE and PR3 assist in the destruction of phagocytosed microorganisms, cleave the important connective-tissue protein elastin, and generate chemotactic activities by forming alpha 1-proteinase inhibitor complexes and elastin peptides. AZU is cytotoxic to certain microorganisms and chemotactic for monocytes. All three proteins are produced and packaged into azurophil granules in large quantities during neutrophil differentiation. We have isolated several cosmid clones each of which contains the functional genes for AZU, PR3, and NE in this order. The PR3 gene is separated by 8 kilobases from the 3' end of the AZU gene and by 3 kilobases from the 5' end of the NE gene. We report a physical map of the gene cluster, its location on chromosome 19pter, and the exon-intron organization of the AZU and PR3 genes. Our fluorescence in situ hybridization studies disprove the previous chromosomal assignment of the human NE gene to 11q14. The five exons of AZU and PR3 are organized like those of NE and other granule-associated serine proteases of hematopoietic cells. NE, PR3, and AZU are coordinately downregulated in the premonocytic cell line U937 during induced terminal differentiation. The cluster-like physical organization of these genes and concerted regulation during hematopoietic differentiation suggests that they are located in a developmentally activated chromatin domain promoting high-level, cell-specific expression in the monocyte-myelocyte lineage.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Spitznagel JK. Antibiotic proteins of human neutrophils. J Clin Invest. 1990 Nov;86(5):1381–1386. [PMC free article] [PubMed]
  • Lehrer RI, Ganz T. Antimicrobial polypeptides of human neutrophils. Blood. 1990 Dec 1;76(11):2169–2181. [PubMed]
  • Kao RC, Wehner NG, Skubitz KM, Gray BH, Hoidal JR. Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. J Clin Invest. 1988 Dec;82(6):1963–1973. [PMC free article] [PubMed]
  • Lüdemann J, Utecht B, Gross WL. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme. J Exp Med. 1990 Jan 1;171(1):357–362. [PMC free article] [PubMed]
  • Rao NV, Wehner NG, Marshall BC, Gray WR, Gray BH, Hoidal JR. Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase. Structural and functional properties. J Biol Chem. 1991 May 25;266(15):9540–9548. [PubMed]
  • Smedly LA, Tonnesen MG, Sandhaus RA, Haslett C, Guthrie LA, Johnston RB, Jr, Henson PM, Worthen GS. Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest. 1986 Apr;77(4):1233–1243. [PMC free article] [PubMed]
  • Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989 Feb 9;320(6):365–376. [PubMed]
  • Crystal RG. The alpha 1-antitrypsin gene and its deficiency states. Trends Genet. 1989 Dec;5(12):411–417. [PubMed]
  • Pereira HA, Shafer WM, Pohl J, Martin LE, Spitznagel JK. CAP37, a human neutrophil-derived chemotactic factor with monocyte specific activity. J Clin Invest. 1990 May;85(5):1468–1476. [PMC free article] [PubMed]
  • Kallenberg CG, Tervaert JW, van der Woude FJ, Goldschmeding R, von dem Borne AE, Weening JJ. Autoimmunity to lysosomal enzymes: new clues to vasculitis and glomerulonephritis? Immunol Today. 1991 Feb;12(2):61–64. [PubMed]
  • Jennette JC, Charles LA, Falk RJ. Antineutrophil cytoplasmic autoantibodies: disease associations, molecular biology, and pathophysiology. Int Rev Exp Pathol. 1991;32:193–221. [PubMed]
  • Bories D, Raynal MC, Solomon DH, Darzynkiewicz Z, Cayre YE. Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells. Cell. 1989 Dec 22;59(6):959–968. [PubMed]
  • Jenne DE, Tschopp J, Lüdemann J, Utecht B, Gross WL. Wegener's autoantigen decoded. Nature. 1990 Aug 9;346(6284):520–520. [PubMed]
  • Porteu F, Brockhaus M, Wallach D, Engelmann H, Nathan CF. Human neutrophil elastase releases a ligand-binding fragment from the 75-kDa tumor necrosis factor (TNF) receptor. Comparison with the proteolytic activity responsible for shedding of TNF receptors from stimulated neutrophils. J Biol Chem. 1991 Oct 5;266(28):18846–18853. [PubMed]
  • Mueller SG, Paterson AJ, Kudlow JE. Transforming growth factor alpha in arterioles: cell surface processing of its precursor by elastases. Mol Cell Biol. 1990 Sep;10(9):4596–4602. [PMC free article] [PubMed]
  • Farley D, Salvesen G, Travis J. Molecular cloning of human neutrophil elastase. Biol Chem Hoppe Seyler. 1988 May;369 (Suppl):3–7. [PubMed]
  • Takahashi H, Nukiwa T, Basset P, Crystal RG. Myelomonocytic cell lineage expression of the neutrophil elastase gene. J Biol Chem. 1988 Feb 15;263(5):2543–2547. [PubMed]
  • Salvesen G, Farley D, Shuman J, Przybyla A, Reilly C, Travis J. Molecular cloning of human cathepsin G: structural similarity to mast cell and cytotoxic T lymphocyte proteinases. Biochemistry. 1987 Apr 21;26(8):2289–2293. [PubMed]
  • Campanelli D, Melchior M, Fu Y, Nakata M, Shuman H, Nathan C, Gabay JE. Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils. J Exp Med. 1990 Dec 1;172(6):1709–1715. [PMC free article] [PubMed]
  • Morgan JG, Sukiennicki T, Pereira HA, Spitznagel JK, Guerra ME, Larrick JW. Cloning of the cDNA for the serine protease homolog CAP37/azurocidin, a microbicidal and chemotactic protein from human granulocytes. J Immunol. 1991 Nov 1;147(9):3210–3214. [PubMed]
  • Almeida RP, Melchior M, Campanelli D, Nathan C, Gabay JE. Complementary DNA sequence of human neutrophil azurocidin, an antibiotic with extensive homology to serine proteases. Biochem Biophys Res Commun. 1991 Jun 14;177(2):688–695. [PubMed]
  • Takahashi H, Nukiwa T, Yoshimura K, Quick CD, States DJ, Holmes MD, Whang-Peng J, Knutsen T, Crystal RG. Structure of the human neutrophil elastase gene. J Biol Chem. 1988 Oct 15;263(29):14739–14747. [PubMed]
  • Farley D, Travis J, Salvesen G. The human neutrophil elastase gene. Analysis of the nucleotide sequence reveals three distinct classes of repetitive DNA. Biol Chem Hoppe Seyler. 1989 Jul;370(7):737–744. [PubMed]
  • Nakamura H, Okano K, Aoki Y, Shimizu H, Naruto M. Nucleotide sequence of human bone marrow serine protease (medullasin) gene. Nucleic Acids Res. 1987 Nov 25;15(22):9601–9602. [PMC free article] [PubMed]
  • Hohn PA, Popescu NC, Hanson RD, Salvesen G, Ley TJ. Genomic organization and chromosomal localization of the human cathepsin G gene. J Biol Chem. 1989 Aug 15;264(23):13412–13419. [PubMed]
  • Jenne DE, Zimmer M, Garcia-Sanz JA, Tschopp J, Lichter P. Genomic organization and subchromosomal in situ localization of the murine granzyme F, a serine protease expressed in CD8+ T cells. J Immunol. 1991 Aug 1;147(3):1045–1052. [PubMed]
  • Pohl J, Pereira HA, Martin NM, Spitznagel JK. Amino acid sequence of CAP37, a human neutrophil granule-derived antibacterial and monocyte-specific chemotactic glycoprotein structurally similar to neutrophil elastase. FEBS Lett. 1990 Oct 15;272(1-2):200–204. [PubMed]
  • Poustka A, Rackwitz HR, Frischauf AM, Hohn B, Lehrach H. Selective isolation of cosmid clones by homologous recombination in Escherichia coli. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4129–4133. [PMC free article] [PubMed]
  • Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. [PMC free article] [PubMed]
  • Rackwitz HR, Zehetner G, Murialdo H, Delius H, Chai JH, Poustka A, Frischauf A, Lehrach H. Analysis of cosmids using linearization by phage lambda terminase. Gene. 1985;40(2-3):259–266. [PubMed]
  • Thomas PS. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. [PMC free article] [PubMed]
  • Schleuning WD, Medcalf RL, Hession C, Rothenbühler R, Shaw A, Kruithof EK. Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester-mediated differentiation of U-937 human histiocytic lymphoma cells. Mol Cell Biol. 1987 Dec;7(12):4564–4567. [PMC free article] [PubMed]
  • Lichter P, Tang CJ, Call K, Hermanson G, Evans GA, Housman D, Ward DC. High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science. 1990 Jan 5;247(4938):64–69. [PubMed]
  • Hulsebos T, Schonk D, van Dalen I, Coerwinkel-Driessen M, Schepens J, Ropers HH, Wieringa B. Isolation and characterization of alphoid DNA sequences specific for the pericentric regions of chromosomes 4, 5, 9, and 19. Cytogenet Cell Genet. 1988;47(3):144–148. [PubMed]
  • Faisst S, Meyer S. Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res. 1992 Jan 11;20(1):3–26. [PMC free article] [PubMed]
  • Ephrussi A, Church GM, Tonegawa S, Gilbert W. B lineage--specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science. 1985 Jan 11;227(4683):134–140. [PubMed]
  • Leiden JM. Transcriptional regulation during T-cell development: the alpha TCR gene as a molecular model. Immunol Today. 1992 Jan;13(1):22–30. [PubMed]
  • Heller M, Flemington E, Kieff E, Deininger P. Repeat arrays in cellular DNA related to the Epstein-Barr virus IR3 repeat. Mol Cell Biol. 1985 Mar;5(3):457–465. [PMC free article] [PubMed]
  • Hanson RD, Connolly NL, Burnett D, Campbell EJ, Senior RM, Ley TJ. Developmental regulation of the human cathepsin G gene in myelomonocytic cells. J Biol Chem. 1990 Jan 25;265(3):1524–1530. [PubMed]
  • Hanson RD, Hohn PA, Popescu NC, Ley TJ. A cluster of hematopoietic serine protease genes is found on the same chromosomal band as the human alpha/delta T-cell receptor locus. Proc Natl Acad Sci U S A. 1990 Feb;87(3):960–963. [PMC free article] [PubMed]
  • Haddad P, Jenne D, Tschopp J, Clément MV, Mathieu-Mahul D, Sasportes M. Structure and evolutionary origin of the human granzyme H gene. Int Immunol. 1991 Jan;3(1):57–66. [PubMed]
  • Labbaye C, Musette P, Cayre YE. Wegener autoantigen and myeloblastin are encoded by a single mRNA. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9253–9256. [PMC free article] [PubMed]
  • Welgus HG, Connolly NL, Senior RM. 12-o-Tetradecanoyl-phorbol-13-acetate-differentiated U937 cells express a macrophage-like profile of neutral proteinases. High levels of secreted collagenase and collagenase inhibitor accompany low levels of intracellular elastase and cathepsin G. J Clin Invest. 1986 May;77(5):1675–1681. [PMC free article] [PubMed]
  • Fouret P, du Bois RM, Bernaudin JF, Takahashi H, Ferrans VJ, Crystal RG. Expression of the neutrophil elastase gene during human bone marrow cell differentiation. J Exp Med. 1989 Mar 1;169(3):833–845. [PMC free article] [PubMed]
  • Wilde CG, Snable JL, Griffith JE, Scott RW. Characterization of two azurphil granule proteases with active-site homology to neutrophil elastase. J Biol Chem. 1990 Feb 5;265(4):2038–2041. [PubMed]
  • Campanelli D, Detmers PA, Nathan CF, Gabay JE. Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J Clin Invest. 1990 Mar;85(3):904–915. [PMC free article] [PubMed]
  • Gabay JE, Scott RW, Campanelli D, Griffith J, Wilde C, Marra MN, Seeger M, Nathan CF. Antibiotic proteins of human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5610–5614. [PMC free article] [PubMed]
  • Bode W, Meyer E, Jr, Powers JC. Human leukocyte and porcine pancreatic elastase: X-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry. 1989 Mar 7;28(5):1951–1963. [PubMed]
  • Brendel V, Dohlman J, Blaisdell BE, Karlin S. Very long charge runs in systemic lupus erythematosus-associated autoantigens. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1536–1540. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM record citing PubMed
  • Protein
    Published protein sequences
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...