Disease relevance of Lox

• Lox-targeted mice (LOX(-/-)) died soon after parturition, exhibiting cardiovascular instability with ruptured arterial aneurysms and diaphragmatic rupture [1].
• Mouse Lox was recently shown to be crucial for development of the cardiovascular system because null mice died perinatally of aortic aneurysms and cardiovascular dysfunction [2].
• Early effects of the dose were: prevention of the tremors and spasms seen in untreated mutants, raising to normal and near-normal of caeruloplasmin oxidase and lysyl oxidase activities and pigmentation of skin and fur [3].
• To further understand the mechanism of cadmium toxicity, the mRNA expression, synthesis, post-translational processing, and catalytic activity of lysyl oxidase were examined in cadmium-resistant (CdR) cells and the cadmium-sensitive Swiss mouse 3T3 cells from which they were derived [4].
• Both tools were used to examine the expression of the lysyl oxidase mRNAs and peptides, all within granulomas and cells extracted from infected liver [5].

High impact information on Lox

• GFAP-Cre;Rb(LoxP/LoxP);p53(-/- or LoxP/LoxP) mice developed highly aggressive embryonal tumors of the cerebellum with typical features of medulloblastoma [6].
• To investigate these opposite functions of DC, we generated a Cre/LoxP-based system that allows inducible antigen presentation by DC in vivo [7].
• Therefore, we developed a LoxP/Cre-based conditional mutation approach to test the role of c-myc in mouse embryonic fibroblasts (MEFs) and mature B lymphocytes [8].
• The mechanism of T cell lineage commitment remains controversial; to examine it we deleted the CD4-silencer element in the germ line of a mouse using a combination of gene targeting and Cre/LoxP-mediated recombination [9].
• We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells [10].

Chemical compound and disease context of Lox

• When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma [11].
• However, only chronic liver injury appeared to be associated with fibrosis, increased collagen-bound hydroxyproline content, increased hepatic lysyl oxidase and collagenase activities, as well as with increased serum lysyl oxidase activity [12].

Biological context of Lox

• To address this problem of functional and structural redundancy and to determine the role of LOX in the development of tissue integrity, Lox gene expression was deleted by targeted mutagenesis in mice [1].
• The mouse lysyl oxidase gene (Lox) resides on chromosome 18 [13].
• This regulation was found to be reversible and occurred at the transcriptional level determined using lysyl oxidase promoter/reporter gene assays [14].
• The temporal relationship between LOX mRNA and protein, processing of LOXL1 protein, FBLN5 and tropoelastin protein, and desmosine content in the vagina suggest that a burst of elastic fiber assembly and cross linking occurs in the vaginal wall postpartum [15].
• Thus, lysyl oxidase appears critical during embryogenesis for structural stability of the aorta and diaphragm and connective tissue development [1].

Anatomical context of Lox

• Southern analysis of a panel of Chinese hamster x mouse somatic cell hybrids was utilized to assign the lysyl oxidase gene (Lox) to mouse Chromosome 18 [13].
• Autocrine growth factor regulation of lysyl oxidase expression in transformed fibroblasts [14].
• Data support that an FGF-2 autocrine pathway inhibits lysyl oxidase transcription in the tumorigenic-transformed RS485 cell line [14].
• The data together demonstrate that TNF-alpha does not inhibit collagen synthesis but does inhibit the expression and activity of lysyl oxidase in osteoblasts, thereby contributing to perturbed collagen cross-linking and accumulation [16].
• Lysyl oxidase in addition has tumor suppressor activity, and phenotypic reversion of transformed cell lines is accompanied by increased lysyl oxidase expression [14].

Associations of Lox with chemical compounds

• Autocrine pathways were blocked with suramin, a general inhibitor of growth factor receptor binding, and resulted in more than a 10-fold increase in lysyl oxidase expression and proenzyme production [14].
• Treatment of ras-transformed cells with interferon-alpha with or without retinoic acid results in their persistent reversion to a non-transformed state that is dependent on the restoration of LO expression [17].
• Transformation of revertant murine cells by 5-azacytidine results in rapid inhibition of lysyl oxidase expression [17].
• Lysyl oxidase (LO), which catalyzes the oxidation of lysine residues, was previously shown to have anti-oncogenic activity on ras-transformed cells [18].
• Notably, lung lysyl oxidase activity is markedly stimulated in rats exposed to cadmium vapors [4].

Enzymatic interactions of Lox

• The lysyl oxidase catalyzes the first step of collagen and elastin enzymatic cross-linking and appears to be a crucial factor in stabilizing the neosynthesized extracellular matrix in the liver [5].

Regulatory relationships of Lox

• Importantly, LO blocked membrane localization of Akt and PDK1 in Ras-transformed cells [18].
• The full 2 kb murine LOX promoter was very active in 3T6-5 myofibroblast-like cells (MFLC) and vascular smooth muscle cells (SMC) and was inhibited in ras-transformed fibroblasts [19].
• Expression of lysyl oxidase was almost completely down-regulated in two clones of H-ras-transformed 208F cells (FE-8 and FE-56) [20].
• Data show that BMP-1 Inhibitor dose dependently inhibits lysyl oxidase activation by up to 50% in undifferentiated proliferating cells [21].

Other interactions of Lox

• Regulation of collagen deposition and lysyl oxidase by tumor necrosis factor-alpha in osteoblasts [16].
• Finally, the addition of FGF-2 to suramin-treated cells completely reversed suramin stimulation of lysyl oxidase mRNA levels [14].
• Thus, the lysyl oxidase propeptide, which is released during extracellular proteolytic processing of pro-lysyl oxidase, functions to inhibit ras-dependent cell transformation [22].
• LO is expressed in NIH3T3 cells, but only very low levels are observed after NIH 3T3 is transformed by c-H-ras or one of several other oncogenes [17].
• Processing of the LOX proteins by BMP-1 and possibly other mechanisms may result in multiple functional forms [23].

Analytical, diagnostic and therapeutic context of Lox

• In Lox(-/-) fetuses, Doppler ultrasonography revealed increased impedance in the umbilical artery, descending aorta, and intracranial artery blood velocity waveforms, decreased mean velocities across cardiac inflow and outflow regions, and increased pulsatility in ductus venosus blood velocity waveforms [24].
• In light microscopy, hazy and unruffled elastic lamellae in the Lox(-/-) aortas were observed, and electron microscopy of the aortic walls of the Lox(-/-) fetuses showed highly fragmented elastic fibers and discontinuity in the smooth muscle cell layers in Lox(-/-) fetuses [24].
• At that time systolic blood pressure, heart rate, and aortic diameters were measured, and the entire aorta from each mouse was subjected to a bioassay for LO activity [25].
• Molecular cloning of the cDNA revealed it to be identical to the ras recision gene (rrg), for lysyl oxidase [26].
• In this study, we examined LOX localization in wild type rat and mouse brain sections using immunohistochemistry coupled with laser-scanning confocal microscope [27].

References