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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  126. Kongress der Deutschen Gesellschaft für Chirurgie; 20090428-20090501; München; DOC09dgch11099 /20090423/
    Publication Date: 2009-05-06
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
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    Springer International Publish
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  • 3
    Keywords: SPECTRA ; EXPRESSION ; IN-VITRO ; Germany ; VITRO ; GENE ; GENES ; PROTEIN ; PROTEINS ; PATIENT ; FAMILY ; SKIN ; SEQUENCE ; chromosome ; ACID ; IDENTIFICATION ; MUTATION ; MUTATIONS ; EPIDERMAL DIFFERENTIATION ; PHENOTYPE ; point mutation ; ARACHIDONIC-ACID ; EUROPE ; NOMENCLATURE ; CHROMOSOME 17P13.1 ; GENE-PRODUCT ; molecular ; ENZYME-ACTIVITIES ; ENZYME ; MISSENSE MUTATION ; MUTANTS ; recombinant protein ; SUBFAMILY ; ALOX12B ; ALOXE3 ; COLLODION BABY ; congenital ichthyosis ; genodermatosis ; genotype/phenotype correlation ; hepoxilin ; HEPOXILINS ; LAMELLAR ICHTHYOSIS ; lipoxygenase
    Abstract: Autosomal,recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI. have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R-LOX and eLOX3 respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)-HPETE to the corresponding epoxyalcohol, 8(R)-hydroxy,11(R),12(R)-epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease-causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis
    Type of Publication: Journal article published
    PubMed ID: 16116617
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  • 4
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; carcinoma ; CELL ; GENE ; GENES ; ACTIVATION ; MECHANISM ; CONTRAST ; mechanisms ; SEQUENCE ; SEQUENCES ; ALPHA ; ACID ; gene expression ; PROMOTER ; prostate cancer ; oligonucleotides ; CANCER-CELLS ; CARCINOMA-CELLS ; EPITHELIAL-CELLS ; FATTY-ACIDS ; adenocarcinoma ; PPAR-GAMMA ; BINDING PROTEIN ; PROSTATE-CANCER CELLS ; gene regulation ; FRAGMENT ; ANDROGEN ; NUCLEAR RECEPTOR ; 15-lipoxygenase-2 ; peroxisome proliferator-activated receptor gamma ; ROR-ALPHA
    Abstract: An inverse relationship exists between the expression of 15-lipoxygenase-2 (15-LOX-2) and peroxisome proliferator-activated receptor c (PPARc) in normal prostate epithelial cells (PrECs) compared with their expression in prostate carcinoma cells (PC-3). The reason for this difference, however, is unknown. We hypothesized that this inverse expression partly involves the 15-LOX-2 promoter and 15-S-hydroxyeicosatetraenoic acid (15-(S)HETE), a product of 15- LOX-2 that binds to PPARc. We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (-618/+177) that can interact with PPARc. After forced expression of wild-type PPARc, 15-(S)-HETE (1 mu M) decreased F-5 reporter activity in PrECs whereas forced expression of 15-LOX-2 resulted in 15-(S)-HETE production which enhanced F-5 activity in PC-3. In contrast, the expression of dominant-negative PPARc reversed the transcriptional activation of F-5 by enhancing it 202-fold in PrEC or suppressing it in PC-3; the effect in PC-3 was positively increased 150-fold in the presence of 15-(S)-HETE (1 mu M). Peroxisome proliferator-activated receptor c interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (-560/-596 bp) oligonucleotides. In gelshift analyses PPARc and orphan receptor ROR alpha were shown to interact with the F-5 fragment in PC-3 cells. These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARc to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells
    Type of Publication: Journal article published
    PubMed ID: 16682954
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  • 5
    Keywords: EXPRESSION ; tumor ; CELL ; COMBINATION ; Germany ; DEATH ; CLONING ; GENE ; DIFFERENTIATION ; MICE ; INDUCTION ; animals ; KERATINOCYTES ; SKIN ; METABOLITES ; IDENTIFICATION ; HUMANS ; MUTATIONS ; CHROMOSOMAL LOCALIZATION ; epidermal barrier ; TERMINAL DIFFERENTIATION ; keratinocyte ; development ; lipoxygenase ; animal ; GENOMIC STRUCTURE ; peroxisome proliferator activated receptor ; ichthyosis ; RECESSIVE CONGENITAL ICHTHYOSIS ; 12(R)-LIPOXYGENASE ; adipogenesis
    Abstract: 12R-lipoxygenase (12R-LOX) and epidermis-type LOX-3 (eLOX-3) are novel members of the multigene family of mammalian LOX. A considerable gap exists between the identification of these enzymes and their biologic function. Here, we present evidence that 12R-LOX and eLOX-3, acting in sequence, and eLOX-3 in combination with another, not yet identified LOX are critically involved in terminal differentiation of keratinocytes and adipocytes, respectively. Mutational inactivation of 12R-LOX and/or eLOX-3 has been found to be associated with development of an inherited ichthyosiform skin disorder in humans and genetic ablation of 12R-LOX causes a severe impairment of the epidermal lipid barrier in mice leading to post-natal death of the animals. In preadipocytes, a LOX-dependent PPAR gamma activating ligand is released into the cell supernatant early upon induction of differentiation and available evidence indicates that this ligand is an eLOX-3-derived product. In accordance with this data is the observation that forced expression of eLOX-3 enhances adipocyte differentiation. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17164140
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  • 6
    Keywords: EXPRESSION ; Germany ; PATHWAY ; COMMON ; COHORT ; EPIDEMIOLOGY ; GENE ; GENES ; DIFFERENTIATION ; PATIENT ; FAMILY ; DISORDER ; MOUSE ; IDENTIFICATION ; MUTATION ; MUTATIONS ; PHENOTYPE ; CHROMOSOMAL LOCALIZATION ; molecular epidemiology ; HETEROGENEITY ; DISORDERS ; FAMILIES ; USA ; GENOMIC STRUCTURE ; GENETIC-HETEROGENEITY ; EPIDERMIS-TYPE LIPOXYGENASES ; 12R-LIPOXYGENASE ; 12(R)-LIPOXYGENASE ALOX12B ; ERYTHRODERMA
    Abstract: In recent years several new genes for autosomal recessive congenital ichthyosis (ARCI) have been identified. However, little is known about the molecular epidemiology and pathophysiology of this genetically and clinically heterogeneous group of severe disorders of keratinization. ARCI is characterized by intense scaling of the whole integument often associated with erythema. We and others have shown that mutations in ALOX12B and ALOXE3, coding for the lipoxygenases 12R-LOX and eLOX-3 predominantly synthesized in the epidermis, can underlie this rare condition. Here we have surveyed a large group of 250 patients with ARCI for mutations in these two genes. We have identified 11 different previously unreported mutations in ALOX12B and ALOXE3 in 21 ARCI patients from 19 unrelated families and demonstrated that mutations in the two genes are the second most common cause for ARCI in this cohort of patients. Examination of the molecular data revealed allelic heterogeneity for ALOX12B and two mutational hotspots in ALOXE3. Functional analysis of all missense mutations and a splice site mutation demonstrated that complete loss of function of the enzymes underlies the phenotype. Our findings further establish the pivotal role of the 12-lipoxygenase pathway during epidermal differentiation. Journal of Investigative Dermatology (2009) 129, 1421-1428; doi:10.1038/jid.2008.409; published online 8 January 2009
    Type of Publication: Journal article published
    PubMed ID: 19131948
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  • 7
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    Prostaglandins and Other Lipid Mediators 68-69 (Spec. Iss.), 235-243 
    Keywords: EXPRESSION ; MOUSE SKIN ; FATTY-ACIDS ; TUMOR PROMOTION ; POSITIONAL SPECIFICITY ; CHROMATOGRAPHY MASS-SPECTROMETRY ; LIPOXYGENASES ; HYDROXY-EICOSATETRAENOIC ACIDS ; 8-LIPOXYGENASE ; 8S-LIPOXYGENASE
    Abstract: The recently identified mouse 8(S)-lipoxygenase almost exclusively directs oxygen insertion into the 8(S) position of arachidonic acid and, with lower efficiency, into the 9(S) position of linoleic acid. The protein of 677 amino acids displays 78% sequence identity to human 15(S)-lipoxygenase-2 which is considered to be its human orthologue. The 8(S)-lipoxygenase gene, Alox15b, consisting of 14 exons and spanning 14.5 kb is located within a gene cluster of related epidermis-type lipoxygenases at the central region of mouse chromosome 11. 8(S)-Lipoxygenase is predominantly expressed in stratifying epithelia of mice, constitutively in the hair follicle, forestomach, and foot-sole and inducible in the back skin with strain-dependent variations. The expression is restricted to terminally differentiating keratinocytes, in particular the stratum granulosum and 8(S)-lipoxygenase activity seems to be involved in terminal differentiation of mouse epidermis. Tumor-specific up-regulation of 8(S)-lipoxygenase expression and activity indicate a critical role of this enzyme in malignant progression during tumor development in mouse skin.
    Type of Publication: Journal article published
    PubMed ID: 12432921
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  • 8
    Keywords: EXPRESSION ; GENE ; ACQUISITION ; MUTATION ; CHROMOSOMAL LOCALIZATION ; ALOX12B ; GENOMIC STRUCTURE ; RECESSIVE CONGENITAL ICHTHYOSIS ; ADIPOCYTE DIFFERENTIATION ; 12R-LIPOXYGENASE
    Abstract: Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R-LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway.
    Type of Publication: Journal article published
    PubMed ID: 22832496
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  • 9
    Keywords: CELLS ; GENES ; DIFFERENTIATION ; MICE ; PPAR-GAMMA ; placenta ; TROPHOBLAST ; MASH2
    Abstract: Metabolites of the epidermal lipoxygenase-3 (eLOX-3) are involved in various metabolic pathways. Most unexpectedly, intra-amniotic delivery of eLOX-3 to mice at gestational day 14.5, both via an adenoviral vector and as recombinant protein, resulted in fetal growth restriction and intrauterine death. Periodic acid-Schiff staining and RT-PCR analysis of placentae from fetuses exposed to eLOX-3 indicated a lack of glycogen trophoblasts in the junctional zone. Placenta-specific gene expression was altered. Thus, the observed prenatal toxicity of eLOX-3 could be due to a strong effect on placental development.
    Type of Publication: Journal article published
    PubMed ID: 25043671
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  • 10
    Keywords: SYSTEM ; TOOL ; validation ; INDEX ; score ; CONSENSUS ; DERMATITIS ; AREA ; ATOPIC ECZEMA SEVERITY ; OUTCOME MEASURES
    Abstract: Background Autosomal recessive congenital ichthyoses (ARCIs) are keratinization disorders caused by impaired skin barrier function. Mutations in the genes encoding the lipoxygenases 12R-LOX and eLOX-3 are the second most common cause of ARCIs. In recent years, human skin equivalents recapitulating the ARCI phenotype have been established. Objectives To develop a murine organotypic tissue culture model for ARCI. Methods Epidermal keratinocytes were isolated from newborn 12R-LOX-deficient mice and cocultivated with mouse dermal fibroblasts embedded in a scaffold of native collagen type I. Results With this experimental set-up the keratinocytes formed a well-organized multilayered stratified epithelium resembling skin architecture in vivo. All epidermal layers were present and the keratinocytes within showed the characteristic morphological features. Markers for differentiation and maturation indicated regular epidermal morphogenesis. The major components of epidermal structures were expressed, and were obviously processed and assembled properly. In contrast to their wild-type counterparts, 12R-LOX-deficient skin equivalents showed abnormal vesicular structures in the upper epidermal layers correlating with altered lipid composition and increased transepidermal water loss, comparable with 12R-LOX-deficient mice. Conclusions The mouse skin equivalents faithfully recapitulate the 12R-LOX-deficient phenotype observed in vivo, classifying them as appropriate in vitro models to study molecular mechanisms involved in the development of ARCI and to evaluate novel therapeutic agents. In contrast to existing human three-dimensional skin models, the generation of these murine models is not constrained by a limited supply of material and does not depend on in vitro expansion and/or genetic manipulations that could result in inadvertent genotypic and phenotypic alterations.
    Type of Publication: Journal article published
    PubMed ID: 25078898
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