Regulation of cellular 15-lipoxygenase activity on pretranslational, translational, and posttranslational levels.
In mammalian cells, enzymatic lipid peroxidation catalyzed by 12/15-lipoxygenases is regulated by pretranslational, translational, and posttranslational processes. In rabbits, rats, and mice induction of experimental anemia leads to a systemic up-regulation of 12/15-lipoxygenases expression. In addition, interleukins-4 and -13 were identified as strong up-regulators of this enzyme in human and murine monocyte/macrophages and in the lung carcinoma cell line A549, and the interleukin-4(13) cell surface receptor as well as the signal transducer and activator of transcription 6 (STATG) appears to be involved in the signal transduction cascade. On the level of translation, 15-lipoxygenase synthesis is blocked by the binding of regulatory proteins to a characteristic guanine-cytosine-rich repetitive element in the 3'-untranslated region of the rabbit 15-lipoxygenase mRNA, and the formation of such 15-lipoxygenase mRNA/protein complexes was identified as molecular reason for the translational inactivity of the 15-lipoxygenase mRNA in immature red blood cells. However, proteolytic breakdown of the regulatory proteins which were recently identified as hnRNP K and hnRNP E1 overcomes translational inhibition during later stages of reticulocyte maturation. For maximal intracellular activity, 12/15-lipoxygenases require a rise in cytosolic calcium concentration inducing a translocation of the enzyme from the cytosol to cellular membranes as well as small amounts of preformed hydroperoxides which act as essential activators of the enzymes. 12/15-Lipoxygenases undergo irreversible suicide inactivation during fatty acid oxygenation, and this process may be considered an element of down-regulation of enzyme activity. Suicide inactivation and proteolytic breakdown may contribute to the disappearance of functional 12/15-lipoxygenase at later stages of erythropoiesis.
Institute of Biochemistry, University Clinics Charité, Humboldt University, Berlin, Germany. hartmut.kuehn@rz.hu-berlin.de
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H
Kühn
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Heydeck
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R
Brinckman
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Trebus
D000740:Anemia / Q000097:blood / Q000201:enzymology; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000097:blood* / Q000235:genetics*; D004912:Erythrocytes / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D051381:Rats; D012156:Reticulocytes / Q000201:enzymology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D001093:Arachidonate 15-Lipoxygenase