Lysyl oxidase

Lysyl oxidase
Identifiers
Symbols LOX; MGC105112
External IDs OMIM: 153455 MGI: 96817 HomoloGene: 1741 GeneCards: LOX Gene
EC number 1.4.3.13
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 4015 16948
Ensembl ENSG00000113083 ENSMUSG00000024529
UniProt P28300 Q3TLP7
RefSeq (mRNA) NM_001178102.1 NM_010728.2
RefSeq (protein) NP_001171573.1 NP_034858.2
Location (UCSC) Chr 5:
121.4 – 121.41 Mb		 Chr 18:
52.68 – 52.69 Mb
PubMed search [1] [2]

Lysyl oxidase also known as protein-lysine 6-oxidase is a protein that, in humans, is encoded by the LOX gene.[1][2] Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.

Contents

Function

Lysyl oxidase is an extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues in collagen and elastin precursors.[3][4] These aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin.[1]

Complex cross-links are formed in collagen (pyridinolines derived from three lysine residues) and in elastin (desmosines derived from four lysine residues) that differ in structure.[5]

The importance of lysyl oxidase-derived cross-linking was established from animal studies in which lysyl oxidase was inhibited either by nutritional copper-deficiency or by supplementation of diets with β-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase.[6] This resulted in lathyrism, characterized by poor bone formation and strength, hyperextensible skin, weak ligaments, and increased occurrence of aortic aneurysms. These abnormalities correlated well with decreased cross-linking of collagen and elastin.[7]

Clinical significance

LOX expression is regulated by hypoxia-inducible factors (HIFs), and, hence, LOX expression is often upregulated in hypoxic breast and head and neck tumors. Patients with high LOX-expressing tumors have poor overall survival. Furthermore, inhibition of LOX has been demonstrated to eliminate metastases in mice. Secreted LOX is responsible for the invasive properties of hypoxic cancer cells through focal adhesion kinase activity and cell-to-matrix adhesion. LOX may be required to create a niche permissive for metastatic growth and, thus, may be required for hypoxia-induced metastasis.[8]

In a rodent model of breast cancer, a small-molecule or antibody inhibitors of LOX abolished metastasis.[9] LOX secreted by hypoxic breast tumor cells crosslinks collagen in the basement membrane and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells in turn adhere to crosslinked collagen and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion of metastasizing tumor cells. In contrast, LOX inhibition prevents CD11b+ cell recruitment and metastatic growth.[10]

Hence, inhibitors of the LOX enzyme may be useful in preventing tumor progression and metastasis as well as treating other fibrotic disease involving remodeling of the extracellular matrix, including neurodegenerative and cardiovascular diseases.[11]

See also

References

  1. ^ a b "Entrez Gene: LOX lysyl oxidase". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4015. 
  2. ^ Hämäläinen ER, Jones TA, Sheer D, Taskinen K, Pihlajaniemi T, Kivirikko KI (November 1991). "Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2". Genomics 11 (3): 508–16. doi:10.1016/0888-7543(91)90057-L. PMID 1685472. 
  3. ^ Alberts, Bruce (2002). Molecular biology of the cell. New York: Garland Science. pp. 1099. ISBN 0-8153-3218-1. 
  4. ^ Csiszar K (2001). "Lysyl oxidases: a novel multifunctional amine oxidase family". Prog. Nucleic Acid Res. Mol. Biol. 70: 1–32. doi:10.1016/S0079-6603(01)70012-8. PMID 11642359. 
  5. ^ Siegel RC, Fu JC, Uto N, Horiuchi K, Fujimoto D (October 1982). "Collagen cross-linking: lysyl oxidase dependent synthesis of pyridinoline in vitro: confirmation that pyridinoline is derived from collagen". Biochem. Biophys. Res. Commun. 108 (4): 1546–50. doi:10.1016/S0006-291X(82)80083-1. PMID 6129847. 
  6. ^ Dawson DA, Rinaldi AC, Pöch G (August 2002). "Biochemical and toxicological evaluation of agent-cofactor reactivity as a mechanism of action for osteolathyrism". Toxicology 177 (2-3): 267–84. doi:10.1016/S0300-483X(02)00233-0. PMID 12135629. 
  7. ^ Wilmarth KR, Froines JR (November 1992). "In vitro and in vivo inhibition of lysyl oxidase by aminopropionitriles". J Toxicol Environ Health 37 (3): 411–23. doi:10.1080/15287399209531680. PMID 1359158. 
  8. ^ Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (April 2006). "Lysyl oxidase is essential for hypoxia-induced metastasis". Nature 440 (7088): 1222–6. doi:10.1038/nature04695. PMID 16642001. 
  9. ^ Erler JT, Giaccia AJ (November 2006). "Lysyl oxidase mediates hypoxic control of metastasis". Cancer Res. 66 (21): 10238–41. doi:10.1158/0008-5472.CAN-06-3197. PMID 17079439. 
  10. ^ Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (January 2009). "Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche". Cancer Cell 15 (1): 35–44. doi:10.1016/j.ccr.2008.11.012. PMC 3050620. PMID 19111879. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3050620. 
  11. ^ Rodríguez C, Rodríguez-Sinovas A, Martínez-González J (May 2008). "Lysyl oxidase as a potential therapeutic target". Drug News Perspect. 21 (4): 218–24. doi:10.1358/dnp.2008.21.4.1213351. PMID 18560621. 

Further reading

  • Csiszar K (2001). "Lysyl oxidases: a novel multifunctional amine oxidase family". Prog. Nucleic Acid Res. Mol. Biol. 70: 1–32. doi:10.1016/S0079-6603(01)70012-8. PMID 11642359. 
  • Kagan HM, Li W (2003). "Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell". J. Cell. Biochem. 88 (4): 660–72. doi:10.1002/jcb.10413. PMID 12577300. 
  • Svinarich DM, Twomey TA, Macauley SP, et al. (1992). "Characterization of the human lysyl oxidase gene locus". J. Biol. Chem. 267 (20): 14382–7. PMID 1352776. 
  • Mariani TJ, Trackman PC, Kagan HM, et al. (1992). "The complete derived amino acid sequence of human lysyl oxidase and assignment of the gene to chromosome 5 (extensive sequence homology with the murine ras recision gene)". Matrix 12 (3): 242–8. PMID 1357535. 
  • Murawaki Y, Kusakabe Y, Hirayama C (1992). "Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin". Hepatology 14 (6): 1167–73. doi:10.1002/hep.1840140635. PMID 1683640. 
  • Hämäläinen ER, Jones TA, Sheer D, et al. (1992). "Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2". Genomics 11 (3): 508–16. doi:10.1016/0888-7543(91)90057-L. PMID 1685472. 
  • Konishi A, Iguchi H, Ochi J, et al. (1985). "Increased lysyl oxidase activity in culture medium of nonparenchymal cells from fibrotic livers". Gastroenterology 89 (4): 709–15. PMID 2863189. 
  • Kuivaniemi H, Ala-Kokko L, Kivirikko KI (1986). "Secretion of lysyl oxidase by cultured human skin fibroblasts and effects of monensin, nigericin, tunicamycin and colchicine". Biochim. Biophys. Acta 883 (2): 326–34. PMID 2874833. 
  • Reiser KM, Hennessy SM, Last JA (1988). "Analysis of age-associated changes in collagen crosslinking in the skin and lung in monkeys and rats". Biochim. Biophys. Acta 926 (3): 339–48. PMID 3120785. 
  • Järveläinen H, Halme T, Rönnemaa T (1982). "Effect of cortisol on the proliferation and protein synthesis of human aortic smooth muscle cells in culture". Acta Med. Scand. Suppl. 660: 114–22. PMID 6127904. 
  • Kuivaniemi H, Savolainen ER, Kivirikko KI (1984). "Human placental lysyl oxidase. Purification, partial characterization, and preparation of two specific antisera to the enzyme". J. Biol. Chem. 259 (11): 6996–7002. PMID 6144680. 
  • Lien YH, Stern R, Fu JC, Siegel RC (1984). "Inhibition of collagen fibril formation in vitro and subsequent cross-linking by glucose". Science 225 (4669): 1489–91. doi:10.1126/science.6147899. PMID 6147899. 
  • Yasutake A, Powers JC (1981). "Reactivity of human leukocyte elastase and porcine pancreatic elastase toward peptide 4-nitroanilides containing model desmosine residues. Evidence that human leukocyte elastase is selective for cross-linked regions of elastin". Biochemistry 20 (13): 3675–9. doi:10.1021/bi00516a002. PMID 6912069. 
  • Kim Y, Boyd CD, Csiszar K (1995). "A new gene with sequence and structural similarity to the gene encoding human lysyl oxidase". J. Biol. Chem. 270 (13): 7176–82. doi:10.1074/jbc.270.13.7176. PMID 7706256. 
  • Hämäläinen ER, Kemppainen R, Pihlajaniemi T, Kivirikko KI (1993). "Structure of the human lysyl oxidase gene". Genomics 17 (3): 544–8. doi:10.1006/geno.1993.1369. PMID 7902322. 
  • Forbes EG, Cronshaw AD, MacBeath JR, Hulmes DJ (1994). "Tyrosine-rich acidic matrix protein (TRAMP) is a tyrosine-sulphated and widely distributed protein of the extracellular matrix". FEBS Lett. 351 (3): 433–6. doi:10.1016/0014-5793(94)00907-4. PMID 8082810. 
  • Csiszar K, Mariani TJ, Gosin JS, et al. (1993). "A restriction fragment length polymorphism results in a nonconservative amino acid substitution encoded within the first exon of the human lysyl oxidase gene". Genomics 16 (2): 401–6. doi:10.1006/geno.1993.1203. PMID 8100215. 
  • Vetter U, Weis MA, Mörike M, et al. (1993). "Collagen crosslinks and mineral crystallinity in bone of patients with osteogenesis imperfecta". J. Bone Miner. Res. 8 (2): 133–7. doi:10.1002/jbmr.5650080203. PMID 8442432. 
  • Panchenko MV, Stetler-Stevenson WG, Trubetskoy OV, et al. (1996). "Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase". J. Biol. Chem. 271 (12): 7113–9. doi:10.1074/jbc.271.12.7113. PMID 8636146. 
  • Khakoo A, Thomas R, Trompeter R, et al. (1997). "Congenital cutis laxa and lysyl oxidase deficiency". Clin. Genet. 51 (2): 109–14. doi:10.1111/j.1399-0004.1997.tb02430.x. PMID 9111998. 

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