Cell signaling and gene regulation of human 12(S)-lipoxygenase expression

Human 12(S)-lipoxygenase is a platelet-type 12(S)-lipoxyenase. Its expression is detected in human erythroleukemia cells, human skin epidermal cells and human epidermoid carcinoma A431 cells. Treatment of A431 cells with EGF or PMA induces the gene expression of human 12(S)-lipoxygenase. The induction of gene expression is mediated through the cell signaling of MAPK activation, followed by the induction of c-Jun expression. The transcription factor Sp1 binding to the two Sp1 recognition motifs residing at -158 to 150bp and -123 to 114bp in the gene promoter is found to be essential for both EGF- and PMA-induced gene expression of human 12(S)-lipoxygenase. However, no change of Sp1 binding to GC-rich sequence was observed while no AP-1-binding site can be found in the responsive region of the promoter in EGF- and PMA-induced promoter activation of the human 12(S)-lipoxygenase gene. Since both of the transcription factors c-Jun and Sp1 are prerequisite for EGF and PMA response, interaction between c-Jun and Sp1 may account for the functional regulation of human 12(S)-lipoxygenase gene regulation. The direct and cooperative interaction between c-Jun and Sp1 induced by EGF or PMA activates the expression of the human 12(S)-lipoxygenase gene. Therefore, Sp1 may serve at least in part as a carrier to bring c-Jun to the promoter, thus transactivating the transcriptional activity of the human 12(S)-lipoxygenase gene.