Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.4.3.13 (lysyl oxidase)
 1,248 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that proto-oncoprotein c-Jun is activated in ornithine decarboxylase (ODC)- and RAS-transformed mouse fibroblasts, and that the transformed morphology of these cells can be reversed by expressing the transactivation domain deletion mutant of c-Jun (TAM67). Here, we found that lysyl oxidase (Lox), encoding an extracellular matrix-modifying enzyme, is downregulated in a c-Jun-dependent manner in ODC-transformed fibroblasts (Odc cells). In addition to Lox, the Lox family members Lox-like 1 and 3 (Loxl1 and Loxl3) were found to be downregulated in Odc as well as in RAS-transformed fibroblasts (E4), whereas Lox-like 4 (Loxl4) was upregulated in Odc and downregulated in E4 cells compared to normal N1 fibroblasts. Tetracycline-regulatable LOX re-expression in Odc cells led to inhibition of cell growth and invasion in three-dimensional Matrigel in an activity-independent manner. On the contrary, LOX and especially LOXL2, LOXL3, and LOXL4 were found to be upregulated in several human melanoma cell lines, and LOX inhibitor B-aminopropionitrile inhibited the invasive growth of these cells particularly when co-cultured with fibroblasts in Matrigel. Knocking down the expression of LOX and especially LOXL2 in melanoma cells almost completely abrogated the invasive growth capability. Further, LOXL2 was significantly upregulated in clinical human primary melanomas compared to benign nevi, and high expression of LOXL2 in primary melanomas was associated with formation of metastases and shorter survival of patients. Thus, our studies reveal that inactive pro-LOX (together with Lox propeptide) functions as a tumor suppressor in ODC- and RAS-transformed murine fibroblasts by inhibiting cell growth and invasion, and active LOX and LOXL2 as tumor promoters in human melanoma cells by promoting their invasive growth.
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PMID:Divergent roles of lysyl oxidase family members in ornithine decarboxylase- and RAS-transformed mouse fibroblasts and human melanoma cells. 3070 Oct 28

The cross-linking of structural extracellular matrix (ECM) components, especially fibrillar collagens and elastin, is strongly implicated in fibrosis progression and resistance to fibrosis reversal. Lysyl oxidase family members (LOX and LOXL1 [lysyl oxidase-like 1], LOXL2 [lysyl oxidase-like 2], LOXL3 [lysyl oxidase-like 3], and LOXL4 [lysyl oxidase like 4]) are extracellular copper-dependent enzymes that play a key role in ECM cross-linking, but have also other intracellular functions relevant to fibrosis and carcinogenesis. Although the expression of most LOX family members is elevated in experimental liver fibrosis of diverse etiologies, their individual contribution to fibrosis is incompletely understood. Inhibition of the LOX family as a whole and of LOX, LOXL1, and LOXL2 specifically has been shown to suppress fibrosis progression and accelerate its reversal in rodent models of cardiac, renal, pulmonary, and liver fibrosis. Recent disappointing clinical trials with a monoclonal antibody against LOXL2 (simtuzumab) in patients with pulmonary and liver fibrosis dampened enthusiasm for LOX family member inhibition. However, this unexpected negative outcome may be related to the inefficient antibody, rather than to LOXL2, not qualifying as a relevant antifibrotic target. Moreover, LOX family members other than LOXL2 may prove to be attractive therapeutic targets. In this review, we summarize the structural hallmarks, expression patterns, covalent cross-linking activities, and modes of regulation of LOX family members and discuss the clinical potential of their inhibition to treat fibrosis in general and liver fibrosis in particular.
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PMID:Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis. 3217 58

Articular cartilage remains among the most difficult tissues to regenerate due to its poor self-repair capacity. The lysyl oxidase family (LOX; also termed as protein-lysine 6-oxidase), mainly consists of lysyl oxidase (LO) and lysyl oxidase-like 1-4 (LOXL1-LOXL4), has been traditionally defined as cuproenzymes that are essential for stabilization of extracellular matrix, particularly cross-linking of collagen and elastin. LOX is essential in the musculoskeletal system, particularly cartilage. LOXs-mediated collagen cross-links are essential for the functional integrity of articular cartilage. Appropriate modulation of the expression or activity of certain LOX members selectively may become potential promising strategy for cartilage repair. In the current review, we summarized the advances of LOX in cartilage homeostasis and functioning, as well as copper-mediated activation of LOX through hypoxia-responsive signaling axis during recent decades. Also, the molecular signaling network governing LOX expression has been summarized, indicating that appropriate modulation of hypoxia-responsive-signaling-directed LOX expression through manipulation of bioavailability of copper and oxygen is promising for further clinical implications of cartilage regeneration, which has emerged as a potential therapeutic approach for cartilage rejuvenation in tissue engineering and regenerative medicine. Therefore, targeted regulation of copper-mediated hypoxia-responsive signalling axis for selective modulation of LOX expression may become potential effective therapeutics for enhanced cartilage regeneration and rejuvenation in future clinical implications.
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PMID:Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation. 3319 69

The lysyl oxidase (LOX) family is comprised of LOX and four LOX-like proteins (LOXL1, LOXL2, LOXL3, and LOXL4), and mainly functions in the remodeling of extracellular matrix (ECM) and the cross-linking of collagen and elastic fibers. Recently, a growing body of research has demonstrated that LOX family is critically involved in the regulation of cancer cell proliferation, migration, invasion and metastasis. In this review, we discuss the roles of LOX family members in the development and progression of different types of human cancers. Furthermore, we also describe the potential inhibitors of LOX family proteins and highlight that LOX family might be an important therapeutic target for cancer therapy.
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PMID:Evolving roles of lysyl oxidase family in tumorigenesis and cancer therapy. 3269 13


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