Disease relevance of Alox8

• 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 [1].
• Although mouse 8S-lipoxygenase and human 12R-lipoxygenase are not ortholog genes, we speculate that in mouse and humans the two different enzymes may fulfill equivalent functions in the progression of inflammatory dermatoses [2].
• Leukotriene A synthase activity of purified mouse skin arachidonate 8-lipoxygenase expressed in Escherichia coli [3].

High impact information on Alox8

• Our results with mutation of the conserved Ala to Gly in two S lipoxygenases (mouse 8S-LOX and human 15-LOX-2) and the corresponding Gly-Ala substitution in two R lipoxygenases (human 12R-LOX and coral 8R-LOX) reveal that the basis for R or S stereo-control also involves a switch in the position of oxygenation on the substrate [4].
• Murine 8-lipoxygenase (8-LOX), homologue of the 15-LOX-2 enzyme that is expressed in benign human prostatic epithelium and reduced in Pca, was not detected in wild-type or LPB-Tag prostates as determined by enzyme assay, reverse transcription-PCR, and immunohistochemistry [5].
• 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 [6].
• The cloned 8S-LOX promoter ( approximately 2 kb) in which a transcription initiation site was mapped at -27 from the ATG has neither a TATA box nor a CCAAT box [6].
• Mutation of the corresponding residues in 15-LOX-2 to the 8-LOX sequence changed specificity to 50% oxygenation at C-8 for one amino acid substitution and 70% at C-8 for the double mutant [7].

Biological context of Alox8

• Phorbol ester-inducible mouse 8S-lipoxygenase (8-LOX) and its human homologue, 15S-lipoxygenase-2 (15-LOX-2), share 78% identity in amino acid sequences, yet there is no overlap in their positional specificities [7].
• Collectively, these data suggest that 8S-LOX plays a role as a prodifferentiating, antitumorigenic, and tumor suppressing gene in mouse skin carcinogenesis [1].
• 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 [1].
• Upregulation of 8S-lipoxygenase (8-LOX) in IkappaB-alpha-deficient mice was confirmed at the transcriptional and translational level using ribonuclease protection assay and western analysis [2].
• 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].

Anatomical context of Alox8

• 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 [6].

Associations of Alox8 with chemical compounds

• Mutation of both of these amino acids to the corresponding amino acids in 15-LOX-2 (Asp and Val, respectively) converted the positional specificity from 8S to 90% 15S without yielding any other by-products [7].
• 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 [1].
• To investigate the importance of the residue in mouse 8-LOX structure-function, the serine-558 was replaced by asparagine, histidine, or alanine using oligonucleotide-directed mutagenesis [9].
• Site-directed mutagenesis studies on a putative fifth iron ligand of mouse 8S-lipoxygenase: retention of catalytic activity on mutation of serine-558 to asparagine, histidine, or alanine [9].
• Mouse 8-LOX and its homologues (e.g., human 15-LOX-2) are unique in having a serine in place of the usual Asn or His in this fifth position [9].

Regulatory relationships of Alox8

• 8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes [10].

Analytical, diagnostic and therapeutic context of Alox8

• Molecular cloning and functional expression of a phorbol ester-inducible 8S-lipoxygenase from mouse skin [11].

References