Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes

Bürger, Friederike; Krieg, Peter; Kinzig, Andreas; Schurich, Baerbel; Marks, Friedrich; Fürstenberger, Gerhard

doi:10.1002/(sici)1098-2744(199902)24:2<108::aid-mc5>3.0.co;2-r

Cited by 40 publications

(27 citation statements)

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“…It is a murine homolog of human 15S-LOX-2 and metabolizes AA and LA to 8-HETE and 9-HODE, respectively (Gschwendt et al, 1986;Fu¨rsten-berger et al, 1991;Jisaka et al, 1997;Bu¨rger et al, 1999). However, it uses AA as a preferred substrate.…”

Section: Introductionmentioning

confidence: 99%

“…In normal mouse skin, the level of 8S-LOX expression as well as 8-HETE is nearly undetectable. However, the level is highly elevated after a single topical treatment of 12-O-tetradecanoylphorbol-13-acetate (TPA) (Gschwendt et al, 1986;Fu¨rstenberger et al, 1991;Jisaka et al, 1997) and is further increased in papillomas (Bu¨rger et al, 1999;Nair et al, 2000). In carcinomas, 8S-LOX expression as well as 8-HETE production is back to the level of normal skin (Bu¨rger et al, 1999;Nair et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

et al. 2004

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The levels of 8S-lipoxygenase (8S-LOX) expression and of its arachidonic acid metabolite, 8-hydroxyeicosatetraenoic acid (8-HETE), are highly elevated in the early stages of mouse skin carcinogenesis. On the other hand, several reports showing that 8-HETE is also closely associated with keratinocyte differentiation raise a question concerning the role of 8S-LOX/8-HETE in skin carcinogenesis. To address that question, here we conducted a series of gain-of-function studies. Skin targeted loricrin 8S-LOX/C57BL/6J transgenic mice showed a more differentiated epidermal phenotype as well as a 64% reduced papilloma development in a two-stage skin carcinogenesis protocol. Forced expression of 8S-LOX in MT1/2 cells, a murine papilloma cell line, also caused a more differentiated appearance as well as keratin 1 expression. Overexpression of 8S-LOX in CH72 cells, a murine carcinoma cell line, inhibited cell proliferation by 30% in vitro and by 86% in in vivo xenografts. Exogenous addition of 5 lM 8-HETE to CH72 cells caused cell cycle arrest at the G1 phase. Finally, immunohistochemical analyses showed 8S-LOX protein expression was strictly confined to the differentiated compartment of mouse skin and throughout tumorigenesis. Collectively, these data suggest that 8S-LOX plays a role as a prodifferentiating, antitumorigenic, and tumor suppressing gene in mouse skin carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

et al. 2004

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“…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). 15-LOX-2, on the other hand, was found to accept both AA and LA as substrates to generate 15-HPETE and 13-HPODE (18).…”

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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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“…It metabolizes arachidonic acid as its preferred substrate and produces 8S-HETE. In addition, it was shown that 8S-LOX can convert linoleic acid to 9S-HODE, although with a much lower efficiency (14). So far constitutive enzyme expression has been detected only in mouse brain, footsole, tail, forestomach, and hair follicles (12,13,15).…”

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confidence: 99%

Identification and Characterization of a Phorbol Ester-responsive Element in the Murine 8S-Lipoxygenase Gene

Kim

Muga

Fischer

2004

Journal of Biological Chemistry

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Murine 8S-lipoxygenase (8S-LOX) is a 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible lipoxygenase.That is, it is not detected in normal mouse skin, however, a significant increase in expression is detected in the skin of TPA promotion-sensitive strains of mice after TPA treatment. In this study, we found TPA-induced 8S-LOX mRNA expression is a result of increased transcription in SSIN primary keratinocytes and further investigated transcriptional regulation of 8S-LOX expression by cloning its promoter. The cloned 8S-LOX promoter (ϳ2 kb) in which a transcription initiation site was mapped at ؊27 from the ATG has neither a TATA box nor a CCAAT box. However, the promoter was highly responsive to TPA in TPA promotion-sensitive SSIN but not in TPA promotion-resistant C57BL/6J primary keratinocytes. We then identified a Sp1 binding site located ؊77 to ؊68 from the ATG that is a TPAresponsive element (TRE) of the promoter and that Sp1, Sp2, and Sp3 proteins bind to the TRE. We also found that the binding of these proteins to the TRE was significantly increased by TPA treatment and inhibition of the binding by mithramycin A decreased TPA-induced promoter activity as well as 8S-LOX mRNA expression. These data suggest that increased binding of Sp1, Sp2, and Sp3 to the TRE of the 8S-LOX promoter is a mechanism by which TPA induces 8S-LOX expression in keratinocytes.

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Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes

Cited by 40 publications

References 35 publications

An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

An antitumorigenic role for murine 8S-lipoxygenase in skin carcinogenesis

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

Identification and Characterization of a Phorbol Ester-responsive Element in the Murine 8S-Lipoxygenase Gene

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