Group Dr. Peter Krieg

Role of epidermal lipoxygenases in differentiation and carcinogenesis

Introduction

Lipoxygenases (LOX) are members of a widespread family of dioxygenases occurring in all kingdoms of life. They catalyze the regio- and stereoisomeric hydroperoxidation of polyunsaturated fatty acids to generate, in cooperation with other enzymes, a series of bioactive lipids that are critically involved in the regulation of many physiological and pathophysiological processes including proliferation, differentiation, inflammation and carcinogenesis. With respect to their positional specificity of arachidonic acid oxygenation mammalian LOX have been classified as 5-, 8-, 12-, and 15-LOX. Six different LOX isoforms have been identified in men and seven in mice.
We were among the first to isolate and characterize previously unknown LOX isoforms from skin. These epidermal LOX comprising 15-LOX-2 and its mouse ortholog 8-LOX, 12R-LOX, and eLOX-3 form a distinct subclass of mammalian LOX that were found to be expressed in a differentiation-dependent manner in the epidermis and several other epithelial tissues. Their expression was shown to be deregulated in the course of epithelial carcinogenesis. Our research interests aim at the functional analysis of these enzymes in epidermal differentiation and in cancer development.

Role of 12R-LOX and e-LOX-3 in skin barrier function

12R-LOX and eLOX-3 differ from all other LOX by atypical structural and enzymatic features. 12R-LOX is the only mammalian LOX which forms products with R-chirality and eLOX-3 displays only latent dioxygenase activity but exhibits a dominant hydroperoxide isomerase activity. Both act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives. Interruption of the 12R-LOX/eLOX-3 pathway by loss-of-function mutations in either of the two genes has been shown to be causally linked to the development of autosomal recessive congenital ichthyosis (ARCI). This rare inherited skin disorder is characterized by generalized scaling of the skin and variable erythema caused by a compensatory response to a defective barrier function. Causative mutations have been identified so far in 10 genes, mutations in the two LOX genes have been found in about 15% of ARCI patients thus representing the second most common cause of ARCI.

To elucidate the mechanisms involved in the development of this disorder and its symptoms, we have generated mouse lines with constitutive or inducible ablation of the 12R-LOX and eLOX-3 genes. Constitutive knockout leads to a post-natal lethal phenotype that is due to excessive water loss. The mature 12R-LOX-deficient mouse skin, as analysed in skin grafts and in the conditional knockout model with skin-specific gene inactivation, develops an ichthyosiform phenotype that closely resembles the phenotype observed in ichthyosis patients.  In addition, an organotypic mouse skin model was developed that turned out to be a valuable tool to study the molecular basis for epidermal barrier defects due to LOX-deficiency.

Our studies on the molecular action of LOX showed that the 12R-LOX/eLOX-3 pathway is critically involved in the processing of ω-hydroxy-ceramides, structural lipids that are essential components of the water sealing lipid structures in the stratum corneum. The data indicate that loss of covalently bound ω-hydroxy-ceramides is the decisive defect underlying the diseased skin phenotype of ARCI.

The main goal of ongoing research activities is to decipher the mechanisms of LOX action related to the diseased phenotype and to develop novel molecular approaches towards a therapy of ichthyoses and other conditions of dry and scaly skin.

The 12R-LOX/eLOX-3 pathway is involved in the processing of ω-hydroxy-ceramides that are essential components of the water sealing lipid structures in the stratum corneum. Modified from P. Krieg and G. Fürstenberger (2014) Biochim. Biophys. Acta 1841:390-400.
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