Diversity of mouse lipoxygenases: Identification of a subfamily of epidermal isozymes exhibiting a differentiation‐dependent mRNA expression pattern

Heidt, Markus; Fürstenberger, Gerhard; Vogel, Sonja; Marks, Friedrich; Krieg, Peter

doi:10.1007/s11745-000-0576-0

Cited by 48 publications

(38 citation statements)

References 41 publications

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“…Interestingly, some of the phenotypes observed in the p53+/ m mouse could be correlated to known physiological functions of gene products within the deletion. For example, the deleted region contains a cluster of 3 genes involved in lipid oxygenation, two of which are epidermal lipoxygenases that are expressed primarily in the mouse skin (Boeglin et al ., 1998;Jisaka et al ., 1997;Heidt et al ., 2000). Lipoxygenases have been shown to play important biological roles in mediating adipocyte and skin differentiation, inflammatory responses, and are also expressed in human hair roots (Baer & Green, 1993;Shillabeer et al ., 1998;Furstenberger et al ., 2002;Kantarci & Van Dyke, 2003;Yu et al ., 2003;Yu et al ., 2005).…”

Section: S Venkatachalam Department Of Biochemistry and Cellular Anmentioning

confidence: 99%

Complicating the role of p53 in aging

Gentry

Venkatachalam

2005

Aging Cell

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Recently, we described a p53 mutant mouse model (p53+/m mouse model) that presented a paradox, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan (Tyner et al ., 2002). The p53+/m mice expressed a truncated p53 transcript attached to a leader sequence and showed a moderate increase in p53 activity. Based on this data we hypothesized that enhanced levels of p53 caused the early aging and cancer resistance phenotypes. This hypothesis was attractive as it indirectly implied a 'fine tuning' mechanism of tumor suppressor gene expression to maintain homeostasis at the organismal level (Campisi, 2002;Kirkwood, 2002). Our results also lent support to the evolutionary theory of antagonistic pleiotropy that predicts the deleterious effects of tumor-suppressor genes later in life (Williams, 1957). These observations notwithstanding, the p53+/m mouse model presented a caveat, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan. Studies in model organisms have shown that enhanced resistance to oxidative stress correlates with increased longevity (Johnson et al ., 2002;Murakami et al ., 2003). The tumor suppressor functions of p53 overwhelmingly categorize it as a longevity assurance gene and suggest a synergistic effect on lifespan via tumor free survival of the organism. We show that there are 24 genes deleted in the p53+/m mouse model, complicating the role of p53 in aging and raising the possibility that the phenotypes while resembling 'premature aging-like' symptoms, may not be related to the physiological changes seen during normal aging processes.Along with the partial deletion of one of the p53 alleles, the p53+/m mouse had an upstream deletion that was originally not well defined due to the lack of mouse genome sequence data. This undefined deletion was a major drawback for our hypothesis, leaving open the possibility that the loss of other unidentified genes affected the p53+/m phenotypes. The importance of the upstream deletion was further underlined by the fact that we were unable to generate a p53 m/m mouse from p53+/m crosses even though p53 nullizygosity does not lead to embryonic lethality in mice (Donehower et al ., 1992). To determine the extent of the deletion, we blasted the leader sequence (initially cloned along with the truncated p53 transcript) to the Ensembl mouse genome sequence database and found it to be within the Rho guanine exchange factor 15 ( Arhgef15 ) gene approximately 0.6 Mb upstream of p53.To ascertain the fusion of the Argef15 and p53 alleles, we performed Southern blot assays with multiple restriction enzymes that were common to both the alleles. A schematic representation of the wild-type alleles of p53 and Argef15 is shown in Fig. 1 along with the restriction enzyme sites used for the characterization of the breakpoint present in the p53+/m mouse model. As shown in Fig. 2(a,b), the fusion of the two alleles leads to changes in the restriction fragment length polymorphism (RFLP) patterns of the wt and 'm' alle...

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Section: S Venkatachalam Department Of Biochemistry and Cellular Anmentioning

confidence: 99%

Complicating the role of p53 in aging

Gentry

Venkatachalam

2005

Aging Cell

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“…Mutations in either 12R-LOX or eLOX-3 are associated with autosomal recessive congenital ichthyosis (these disorders will be discussed in detail in the review by Peter Elias) (105-107). Both 12R-LOX and eLOX-3 are localized to the differentiated stratum granulosum layer of the epidermis and convert arachidonic acid to hepoxilin-and trioxilin-like compounds that are believed to play a role in regulating keratinocyte differentiation (105,(108)(109)(110)(111). Moreover, very recent studies have shown that the creation of 12R-LOX-deficient mice results in a severe impairment in barrier function, with the mice dying soon after birth from a defective barrier (108).…”

Section: Jlr: Are There Other Pathways Of Fatty Acid Metabolism That mentioning

confidence: 99%

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Feingold

2007

Journal of Lipid Research

360

366

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The permeability barrier is required for terrestrial life and is localized to the stratum corneum, where extracellular lipid membranes inhibit water movement. The lipids that constitute the extracellular matrix have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Studies have further shown that the elongation and desaturation of fatty acids is also required for barrier homeostasis. The mechanisms that mediate the uptake of extracutaneous lipids by the epidermis are unknown, but keratinocytes express LDL and scavenger receptor class B type 1, fatty acid transport proteins, and CD36. Topical application of physiologic lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders.-Feingold, K. R. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J. Lipid Res.

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“…structural identity with differential epidermal expression (14,15) and a differing product spectrum: 8S-HETE and 9S-HODE (16) versus 15S-HETE and 13S-HODE (21). To explore the functions of these LOXs in keratinocytes, we established inducible expression lines and analyzed the effects of 8-LOX and 15-LOX-2 induction compared with the parental cell line 308 and the reverse Tet repressor expressing Cl20.…”

Section: -Lox-2 and Lox Induced Growth Inhibitionmentioning

confidence: 99%

“…Both enzymes are expressed in the skin of mice and humans but in different compartments of the epithelium. The expression of 15-LOX-2 is restricted to basal keratinocytes, whereas 8-LOX was found to be expressed in suprabasal keratinocytes (14,15). 8-LOX preferentially metabolizes AA to 8-HPETE compared with LA, yielding 9-HPODE (16,17).…”

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confidence: 99%

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

Schweiger

Fürstenberger

Krieg

2007

Journal of Lipid Research

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Human 15-lipoxygenase (LOX)-2 and mouse 8-LOX represent orthologous members of the LOX family but display different positional specificities and tissue distribution. To study the functional role of 15-LOX-2 and 8-LOX in keratinocytes, an inducible Tet-On gene expression system was established in the premalignant mouse keratinocyte cell line 308. Doxycycline (dox)-induced expression of enzymatically active 15-LOX-2 and 8-LOX led to an inhibition of cell growth that was associated with an inhibition of DNA synthesis, as shown by a 15-46% reduction of 5-bromo-2-deoxy-uridine (BrdU) incorporation. The inhibitory effects were increased in the presence of exogenous arachidonic acid. In contrast, addition of linoleic acid or the LOX inhibitor baicalein reversed the growth-inhibitory effects. Treatment of the cells with 15-hydroxyeicosatetraenoic acid (HETE) or 8-HETE resulted in a similar inhibition of BrdU incorporation, whereas 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE, in contrast, had no effects. Doxinduced keratinocytes showed increased levels of reactive oxygen species (ROS). The antioxidant N-acetyl-L-cysteine and a specific inhibitor of p38 mitogen-activated protein kinase, but not of extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase/stress-activated kinases, completely abolished the LOX-induced growth inhibition, indicating a critical role of ROS and p38. Our data suggest that 15-LOX-2 and 8-LOX, although displaying different positional specificity, may use common signaling pathways to induce growth inhibition in premalignant epithelial cells.-Schweiger, D., G. Fü rstenberger, and P. Krieg. Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways. J. Lipid Res.

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Diversity of mouse lipoxygenases: Identification of a subfamily of epidermal isozymes exhibiting a differentiation‐dependent mRNA expression pattern

Cited by 48 publications

References 41 publications

Complicating the role of p53 in aging

Complicating the role of p53 in aging

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

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