Modulation of epidermal tumor development caused by targeted overexpression of epidermis-type 12S-lipoxygenase.
In contrast to other 12S-lipoxygenase (LOX) isoforms expressed in the skin of mice, epidermis-type (e) 12S-LOX was found to be transcriptionally down-regulated in the course of epidermal tumor development in NMRI mice. This may indicate that this enzyme is related to antitumorigenic rather than protumorigenic effects. To test this hypothesis, two transgenic mouse lines were generated that differentially expressed e12S-LOX under the control of the bovine keratin 6 promoter known to be constitutively up-regulated in mouse skin tumors. As compared with the wild-type, low transgene expression correlated with a decreased skin tumor response paralleled by an up-regulation of leukocyte-type 12S-LOX and an accumulation of the linoleic acid derivative 13S-hydroxyoctadecadienoic acid. In contrast, high transgene expression coincided with an increased tumor response paralleled by a strong keratin 6 promoter-driven up-regulation of the transgenic e12S-LOX and an accumulation of the arachidonic acid derivative 12S-hydroxyeicosatetraenoic acid as the predominant LOX product. These results indicate a complex interaction between different LOX isoforms and an opposite role of arachidonic acid and linoleic acid products in the modulation of skin carcinogenesis.
Deutsches Krebsforschungszentrum, Research Program on Tumor Cell Regulation, 69120 Heidelberg, Germany.
Karsten
K
Müller
Malte
M
Siebert
Markus
M
Heidt
Friedrich
F
Marks
Peter
P
Krieg
Gerhard
G
Fürstenberger
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008041:Linoleic Acids / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate; D019076:Transgenes
D002273:Carcinogens; D007527:Isoenzymes; D008041:Linoleic Acids; D012333:RNA, Messenger; C024348:13-hydroxy-9,11-octadecadienoic acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D013755:Tetradecanoylphorbol Acetate