HGNC Approved Gene Symbol: LOXL2
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38) : 8:23,296,897-23,404,120 (from NCBI)
LOXL2 is a member of the lysyl oxidase (LOX; 153455) gene family. LOX is an extracellular, copper-dependent enzyme (EC 1.4.3.13) that initiates the crosslinking of collagens and elastin by catalyzing the oxidative deamination of peptidyl lysine to alpha-aminoadipic-delta-semialdehyde. Members of the LOX family have diverse functions, including tumor suppression and cell adhesion and senescence (summary by Jourdan-Le Saux et al., 1999).
Murano et al. (1991) isolated LOXL2, which they called WS9-14, from human diploid fibroblasts (HDFs) on the basis of its overexpression in cells from subjects with Werner syndrome (WS; 277700). Northern blot analysis detected a 4.2-kb LOXL2 transcript in fibroblasts. Higher levels of LOXL2 expression were observed in both WS and late-passage normal HDFs than in early-passage normal HDFs across the growth cycle from sparse to superconfluent cultures.
Saito et al. (1997) used PCR and 5-prime RACE to obtain a full-length cDNA encoding LOXL2. The predicted 774-amino acid LOXL2 protein contains 3 potential N-linked glycosylation sites and 4 scavenger receptor cysteine-rich (SRCR) domains, which are involved in binding to other cell surface or extracellular molecules. LOXL2 also contains residues conserved among copper-binding proteins. In vitro translation produced an 87-kD LOXL2 protein. Northern blot analysis detected a 3.65-kb LOXL2 transcript in adherent tumor cell lines but not in suspension cell lines. Using cultured fibroblasts, Saito et al. (1997) demonstrated that LOXL2 expression is upregulated in senescent fibroblasts, induced by transforming growth factor beta-1 (TGFB1; 190180) and indomethacin, and inhibited by phorbol ester and retinoic acid. They concluded that LOXL2 is an extracellular matrix component that may be specifically involved in cell adhesion and senescence.
By searching an EST database for sequences with homology to LOX, followed by screening spleen and placenta cDNA libraries, Jourdan-Le Saux et al. (1999) isolated a cDNA encoding LOXL2. This LOXL2 cDNA has sequence homology to the 3-prime end of the WS9-14 cDNA identified by Saito et al. (1997); however, there is no sequence homology to the most 5-prime 780 bp of WS9-14. Jourdan-Le Saux et al. (1999) were unable to isolate any cDNA or genomic clones containing this domain of WS9-14 and hypothesized that this 5-prime part of the WS9-14 cDNA is a PCR product unrelated to the rest of the mRNA and is unlikely to be a transcript derived from the LOXL2 gene. Primer extension analysis identified 2 transcription initiation sites. Northern blot analysis detected a 3.6-kb LOXL2 transcript in all tissues tested except blood leukocytes. The highest steady-state mRNA levels were in placenta, uterus, prostate, and pancreas, and a less-abundant 4.9-kb transcript was detected in heart, liver, and pancreas. In situ hybridization on placental villi and fetal membrane sections detected expression of LOXL2 associated with placental syncytiotrophoblasts.
Using RT-PCR and immunofluorescence analysis, Barry-Hamilton et al. (2010) observed that expression of LOXL2 mRNA and protein were upregulated in diverse solid tumors and fibrotic tissues compared with normal human tissues. A similar upregulation of Loxl2 was observed in mouse models of cancer and pulmonary fibrosis. Treatment with inactivating anti-Loxl2 antibody inhibited pathologic fibroblast activation and reduced disease in the mouse models of cancer and fibrosis. Inhibition of Loxl2 impaired activation of disease-associated fibroblasts, inhibited production of growth factors, and crosslinked collagenous matrix and Tgfb1 signaling. Barry-Hamilton et al. (2010) concluded that LOXL2 may mediate fibroblast activation through enzymatic crosslinking of fibrillar collagen and corresponding increase in local matrix tension, resulting in activation of TGFB1 signaling.
Jourdan-Le Saux et al. (1999) determined that the LOXL2 gene has 11 exons.
Using FISH and radiation hybrid analysis, Jourdan-Le Saux et al. (1998) mapped the LOXL2 gene to chromosome 8p21.3-p21.2.
Barry-Hamilton, V., Spangler, R., Marshall, D., McCauley, S., Rodriguez, H. M., Oyasu, M., Mikels, A., Vaysberg, M., Ghermazien, H., Wai, C., Garcia, C. A., Velayo, A. C., and 11 others. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of pathologic microenvironment. Nature Med. 16: 1009-1017, 2010. [PubMed: 20818376] [Full Text: https://doi.org/10.1038/nm.2208]
Jourdan-Le Saux, C., Le Saux, O., Donlon, T., Boyd, C. D., Csiszar, K. The human lysyl oxidase-related gene (LOXL2) maps between markers D8S280 and D8S278 on chromosome 8p21.2-p21.3. Genomics 51: 305-307, 1998. [PubMed: 9722957] [Full Text: https://doi.org/10.1006/geno.1998.5356]
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. 274: 12939-12944, 1999. [PubMed: 10212285] [Full Text: https://doi.org/10.1074/jbc.274.18.12939]
Murano, S., Thweatt, R., Reis, R. J. S., Jones, R. A., Moerman, E. J., Goldstein, S. Diverse gene sequences are overexpressed in Werner syndrome fibroblasts undergoing premature replicative senescence. Molec. Cell. Biol. 11: 3905-3914, 1991. [PubMed: 1712899] [Full Text: https://doi.org/10.1128/mcb.11.8.3905-3914.1991]
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. 272: 8157-8160, 1997. [PubMed: 9079631] [Full Text: https://doi.org/10.1074/jbc.272.13.8157]