title: Functional role of extracellular signal-regulated kinase activation and c-Jun induction in phorbol ester-induced promoter activation of human 12(S)-lipoxygenase gene.
abstract: The functional role of mitogen-activated protein kinase (MAPK) signaling and c-Jun induction in phorbol 12-myristate 13-acetate (PMA)-induced human 12(S)-lipoxygenase gene expression was studied in human epidermoid carcinoma A431 cells. Among the family of MAPK, PMA only increased the activity of extracellular signal-regulated kinase (ERK). Treatment of cells with PD98059, which is an inhibitor of mitogen-activated protein kinase kinase (MEK), decreased the PMA-induced expression of 12(S)-lipoxygenase. Transfection of cells with Ras, Raf and ERK2 dominant negative mutants inhibited the PMA-induced promoter activation of the 12(S)-lipoxygenase gene in all cases. PMA-induced expression of c-Jun was inhibited by pretreatment with PD98059. Following treatment with PMA, the interaction between c-Jun and simian virus 40 promoter factor 1 (Sp1) in cells increased with time. Enhancement of binding between the c-Jun-Sp1 complex and the Sp1 oligonucleotide was observed in cells treated with PMA, suggesting the possible interaction of c-Jun-Sp1 with GC-rich binding sites in the gene promoter. These results indicate that PMA treatment induced ERK activation mainly through the Raf-MEK-ERK signaling pathway following induction of c-Jun expression, and the formation of the c-Jun-Sp1 complex. Finally, PMA activated the promoter activity of the 12(S)-lipoxygenase gene in cells overexpressing protein kinase C (PKC)delta but not PKCalpha, indicating that PKCdelta played the functional role in mediating the gene activation of 12(S)-lipoxygenase induced by PMA.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
authors.forename: Ben-Kuen
authors.initials: BK
authors.lastname: Chen
authors.forename: Tein-Yi
authors.initials: TY
authors.lastname: Tsai
authors.forename: Huei-Sheng
authors.initials: HS
authors.lastname: Huang
authors.forename: Lei-Chin
authors.initials: LC
authors.lastname: Chen
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
authors.forename: Song-Bor
authors.initials: SB
authors.lastname: Tsai
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
mesh_terms: D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D008084:Lipoxygenase / Q000187:drug effects / Q000235:genetics*; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding; D011493:Protein Kinase C / Q000502:physiology; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D007527:Isoenzymes; D016755:Proto-Oncogene Proteins c-jun; D016329:Sp1 Transcription Factor; D008084:Lipoxygenase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D013755:Tetradecanoylphorbol Acetate