Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Apr 15;355(Pt 2):381–387. doi: 10.1042/0264-6021:3550381

Cloning and characterization of a fourth human lysyl oxidase isoenzyme.

J M Mäki 1, K I Kivirikko 1
PMCID: PMC1221749  PMID: 11284725

Abstract

We report here the complete cDNA sequence and exon-intron organization of the human lysyl oxidase-like (LOXL)3 gene, a new member of the lysyl oxidase (LO) gene family. The predicted polypeptide is 753 amino acids in length, including a signal peptide of 25 residues. The C-terminal region, residues 529-729, contains a LO domain similar to those in the LOX (the first characterized LO isoenzyme), LOXL and LOXL2 polypeptides. It possesses the putative copper binding sequence, and the lysine and tyrosine residues that form the lysyltyrosyl quinone cofactor. The N-terminal region, which is similar to that in LOXL2 but not those in LOX and LOXL, contains four subregions similar to scavenger receptor cysteine-rich domains and a putative nuclear localization signal. Recombinant LOXL3, expressed in HT-1080 cells, was secreted into the culture medium but was not detected by immunofluorescence staining in nuclei. The LOXL3 mRNA is 3.1 kb in size and is expressed in many tissues, the highest levels among the tissues studied being seen in the placenta, heart, ovary, testis, small intestine and spleen.

Full Text

The Full Text of this article is available as a PDF (287.6 KB).

Selected References

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

  1. Aruffo A., Melnick M. B., Linsley P. S., Seed B. The lymphocyte glycoprotein CD6 contains a repeated domain structure characteristic of a new family of cell surface and secreted proteins. J Exp Med. 1991 Oct 1;174(4):949–952. doi: 10.1084/jem.174.4.949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boulikas T. Putative nuclear localization signals (NLS) in protein transcription factors. J Cell Biochem. 1994 May;55(1):32–58. doi: 10.1002/jcb.240550106. [DOI] [PubMed] [Google Scholar]
  3. Casey M. L., MacDonald P. C. Lysyl oxidase (ras recision gene) expression in human amnion: ontogeny and cellular localization. J Clin Endocrinol Metab. 1997 Jan;82(1):167–172. doi: 10.1210/jcem.82.1.3668. [DOI] [PubMed] [Google Scholar]
  4. Contente S., Kenyon K., Rimoldi D., Friedman R. M. Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science. 1990 Aug 17;249(4970):796–798. doi: 10.1126/science.1697103. [DOI] [PubMed] [Google Scholar]
  5. Decitre M., Gleyzal C., Raccurt M., Peyrol S., Aubert-Foucher E., Csiszar K., Sommer P. Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab Invest. 1998 Feb;78(2):143–151. [PubMed] [Google Scholar]
  6. Di Donato A., Lacal J. C., Di Duca M., Giampuzzi M., Ghiggeri G., Gusmano R. Micro-injection of recombinant lysyl oxidase blocks oncogenic p21-Ha-Ras and progesterone effects on Xenopus laevis oocyte maturation. FEBS Lett. 1997 Dec 8;419(1):63–68. doi: 10.1016/s0014-5793(97)01420-8. [DOI] [PubMed] [Google Scholar]
  7. Dimaculangan D. D., Chawla A., Boak A., Kagan H. M., Lazar M. A. Retinoic acid prevents downregulation of ras recision gene/lysyl oxidase early in adipocyte differentiation. Differentiation. 1994 Nov;58(1):47–52. doi: 10.1046/j.1432-0436.1994.5810047.x. [DOI] [PubMed] [Google Scholar]
  8. Dingwall C., Laskey R. A. Nuclear targeting sequences--a consensus? Trends Biochem Sci. 1991 Dec;16(12):478–481. doi: 10.1016/0968-0004(91)90184-w. [DOI] [PubMed] [Google Scholar]
  9. Freeman M., Ashkenas J., Rees D. J., Kingsley D. M., Copeland N. G., Jenkins N. A., Krieger M. An ancient, highly conserved family of cysteine-rich protein domains revealed by cloning type I and type II murine macrophage scavenger receptors. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8810–8814. doi: 10.1073/pnas.87.22.8810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Friedman R. M., Yeh A., Gutman P., Contente S., Kenyon K. Reversion by deletion of transforming oncogene following interferon-beta and retinoic acid treatment. J Interferon Cytokine Res. 1997 Oct;17(10):647–651. doi: 10.1089/jir.1997.17.647. [DOI] [PubMed] [Google Scholar]
  11. Gacheru S. N., Thomas K. M., Murray S. A., Csiszar K., Smith-Mungo L. I., Kagan H. M. Transcriptional and post-transcriptional control of lysyl oxidase expression in vascular smooth muscle cells: effects of TGF-beta 1 and serum deprivation. J Cell Biochem. 1997 Jun 1;65(3):395–407. doi: 10.1002/(sici)1097-4644(19970601)65:3<395::aid-jcb9>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  12. Hajnal A., Klemenz R., Schäfer R. Up-regulation of lysyl oxidase in spontaneous revertants of H-ras-transformed rat fibroblasts. Cancer Res. 1993 Oct 1;53(19):4670–4675. [PubMed] [Google Scholar]
  13. Hämäläinen E. R., Jones T. A., Sheer D., Taskinen K., Pihlajaniemi T., Kivirikko K. I. Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2. Genomics. 1991 Nov;11(3):508–516. doi: 10.1016/0888-7543(91)90057-l. [DOI] [PubMed] [Google Scholar]
  14. Hämäläinen E. R., Kemppainen R., Kuivaniemi H., Tromp G., Vaheri A., Pihlajaniemi T., Kivirikko K. I. Quantitative polymerase chain reaction of lysyl oxidase mRNA in malignantly transformed human cell lines demonstrates that their low lysyl oxidase activity is due to low quantities of its mRNA and low levels of transcription of the respective gene. J Biol Chem. 1995 Sep 15;270(37):21590–21593. doi: 10.1074/jbc.270.37.21590. [DOI] [PubMed] [Google Scholar]
  15. Hämäläinen E. R., Kemppainen R., Pihlajaniemi T., Kivirikko K. I. Structure of the human lysyl oxidase gene. Genomics. 1993 Sep;17(3):544–548. doi: 10.1006/geno.1993.1369. [DOI] [PubMed] [Google Scholar]
  16. Jones N. H., Clabby M. L., Dialynas D. P., Huang H. J., Herzenberg L. A., Strominger J. L. Isolation of complementary DNA clones encoding the human lymphocyte glycoprotein T1/Leu-1. 1986 Sep 25-Oct 1Nature. 323(6086):346–349. doi: 10.1038/323346a0. [DOI] [PubMed] [Google Scholar]
  17. Jourdan-Le Saux C., Tronecker H., Bogic L., Bryant-Greenwood G. D., Boyd C. D., Csiszar K. The LOXL2 gene encodes a new lysyl oxidase-like protein and is expressed at high levels in reproductive tissues. J Biol Chem. 1999 Apr 30;274(18):12939–12944. doi: 10.1074/jbc.274.18.12939. [DOI] [PubMed] [Google Scholar]
  18. Kagan H. M., Trackman P. C. Properties and function of lysyl oxidase. Am J Respir Cell Mol Biol. 1991 Sep;5(3):206–210. doi: 10.1165/ajrcmb/5.3.206. [DOI] [PubMed] [Google Scholar]
  19. Kenyon K., Contente S., Trackman P. C., Tang J., Kagan H. M., Friedman R. M. Lysyl oxidase and rrg messenger RNA. Science. 1991 Aug 16;253(5021):802–802. doi: 10.1126/science.1678898. [DOI] [PubMed] [Google Scholar]
  20. Kenyon K., Modi W. S., Contente S., Friedman R. M. A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome 15q24-q25. J Biol Chem. 1993 Sep 5;268(25):18435–18437. [PubMed] [Google Scholar]
  21. Kim Y., Boyd C. D., Csiszar K. A new gene with sequence and structural similarity to the gene encoding human lysyl oxidase. J Biol Chem. 1995 Mar 31;270(13):7176–7182. doi: 10.1074/jbc.270.13.7176. [DOI] [PubMed] [Google Scholar]
  22. Kim Y., Peyrol S., So C. K., Boyd C. D., Csiszar K. Coexpression of the lysyl oxidase-like gene (LOXL) and the gene encoding type III procollagen in induced liver fibrosis. J Cell Biochem. 1999 Feb 1;72(2):181–188. doi: 10.1002/(sici)1097-4644(19990201)72:2<181::aid-jcb3>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  23. Krebs C. J., Krawetz S. A. Lysyl oxidase copper-talon complex: a model. Biochim Biophys Acta. 1993 Sep 3;1202(1):7–12. doi: 10.1016/0167-4838(93)90056-w. [DOI] [PubMed] [Google Scholar]
  24. Krzyzosiak W. J., Shindo-Okada N., Teshima H., Nakajima K., Nishimura S. Isolation of genes specifically expressed in flat revertant cells derived from activated ras-transformed NIH 3T3 cells by treatment with azatyrosine. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4879–4883. doi: 10.1073/pnas.89.11.4879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kuivaniemi H., Korhonen R. M., Vaheri A., Kivirikko K. I. Deficient production of lysyl oxidase in cultures of malignantly transformed human cells. FEBS Lett. 1986 Jan 20;195(1-2):261–264. doi: 10.1016/0014-5793(86)80172-7. [DOI] [PubMed] [Google Scholar]
  26. Kuivaniemi H., Savolainen E. R., Kivirikko K. I. Human placental lysyl oxidase. Purification, partial characterization, and preparation of two specific antisera to the enzyme. J Biol Chem. 1984 Jun 10;259(11):6996–7002. [PubMed] [Google Scholar]
  27. Li W., Nellaiappan K., Strassmaier T., Graham L., Thomas K. M., Kagan H. M. Localization and activity of lysyl oxidase within nuclei of fibrogenic cells. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12817–12822. doi: 10.1073/pnas.94.24.12817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mello M. L., Contente S., Vidal B. C., Planding W., Schenck U. Modulation of ras transformation affecting chromatin supraorganization as assessed by image analysis. Exp Cell Res. 1995 Oct;220(2):374–382. doi: 10.1006/excr.1995.1328. [DOI] [PubMed] [Google Scholar]
  29. Nielsen H., Brunak S., von Heijne G. Machine learning approaches for the prediction of signal peptides and other protein sorting signals. Protein Eng. 1999 Jan;12(1):3–9. doi: 10.1093/protein/12.1.3. [DOI] [PubMed] [Google Scholar]
  30. Peyrol S., Raccurt M., Gerard F., Gleyzal C., Grimaud J. A., Sommer P. Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma. Am J Pathol. 1997 Feb;150(2):497–507. [PMC free article] [PubMed] [Google Scholar]
  31. Ren C., Yang G., Timme T. L., Wheeler T. M., Thompson T. C. Reduced lysyl oxidase messenger RNA levels in experimental and human prostate cancer. Cancer Res. 1998 Mar 15;58(6):1285–1290. [PubMed] [Google Scholar]
  32. Resnick D., Pearson A., Krieger M. The SRCR superfamily: a family reminiscent of the Ig superfamily. Trends Biochem Sci. 1994 Jan;19(1):5–8. doi: 10.1016/0968-0004(94)90165-1. [DOI] [PubMed] [Google Scholar]
  33. Saito H., Papaconstantinou J., Sato H., Goldstein S. Regulation of a novel gene encoding a lysyl oxidase-related protein in cellular adhesion and senescence. J Biol Chem. 1997 Mar 28;272(13):8157–8160. doi: 10.1074/jbc.272.13.8157. [DOI] [PubMed] [Google Scholar]
  34. Siegel R. C. Lysyl oxidase. Int Rev Connect Tissue Res. 1979;8:73–118. doi: 10.1016/b978-0-12-363708-6.50009-6. [DOI] [PubMed] [Google Scholar]
  35. Smith-Mungo L. I., Kagan H. M. Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol. 1998 Feb;16(7):387–398. doi: 10.1016/s0945-053x(98)90012-9. [DOI] [PubMed] [Google Scholar]
  36. Sullivan K. A., Kagan H. M. Evidence for structural similarities in the multiple forms of aortic and cartilage lysyl oxidase and a catalytically quiescent aortic protein. J Biol Chem. 1982 Nov 25;257(22):13520–13526. [PubMed] [Google Scholar]
  37. Tan R. S., Taniguchi T., Harada H. Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression. Cancer Res. 1996 May 15;56(10):2417–2421. [PubMed] [Google Scholar]
  38. Trackman P. C., Bedell-Hogan D., Tang J., Kagan H. M. Post-translational glycosylation and proteolytic processing of a lysyl oxidase precursor. J Biol Chem. 1992 Apr 25;267(12):8666–8671. [PubMed] [Google Scholar]
  39. Van de Velde H., von Hoegen I., Luo W., Parnes J. R., Thielemans K. The B-cell surface protein CD72/Lyb-2 is the ligand for CD5. Nature. 1991 Jun 20;351(6328):662–665. doi: 10.1038/351662a0. [DOI] [PubMed] [Google Scholar]
  40. Wakasaki H., Ooshima A. Immunohistochemical localization of lysyl oxidase with monoclonal antibodies. Lab Invest. 1990 Sep;63(3):377–384. [PubMed] [Google Scholar]
  41. Wang S. X., Mure M., Medzihradszky K. F., Burlingame A. L., Brown D. E., Dooley D. M., Smith A. J., Kagan H. M., Klinman J. P. A crosslinked cofactor in lysyl oxidase: redox function for amino acid side chains. Science. 1996 Aug 23;273(5278):1078–1084. doi: 10.1126/science.273.5278.1078. [DOI] [PubMed] [Google Scholar]
  42. Whitney G. S., Starling G. C., Bowen M. A., Modrell B., Siadak A. W., Aruffo A. The membrane-proximal scavenger receptor cysteine-rich domain of CD6 contains the activated leukocyte cell adhesion molecule binding site. J Biol Chem. 1995 Aug 4;270(31):18187–18190. doi: 10.1074/jbc.270.31.18187. [DOI] [PubMed] [Google Scholar]
  43. Wu Y., Rich C. B., Lincecum J., Trackman P. C., Kagan H. M., Foster J. A. Characterization and developmental expression of chick aortic lysyl oxidase. J Biol Chem. 1992 Dec 5;267(34):24199–24206. [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES