ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES BY GREEN TEA POLYPHENOLS - POTENTIAL SIGNALING PATHWAYS IN THE REGULATION OF ANTIOXIDANT-RESPONSIVE ELEMENT-MEDIATED PHASE-II ENZYME GENE-EXPRESSION

Green tea polyphenols, major constituents of green tea, are potent che mopreventive agents in a number of experimental models of cancer in an imals, The mechanisms of cancer protection by these agents are not cle ar, but may involve modulation of the enzyme systems responsible for t he detoxification of chemical carcinogens, The present studies show th at a green tea polyphenol extract (GTP) induces chloramphenicol acetyl transferase (CAT) activity in human heptoma HepG2 cells transfected wi th a plasmid construct which contains an antioxidant-responsive elemen t (ARE) and a minimal glutathione S-transferase Ya promoter linked to the CAT reporter gene, This indicates that GTP stimulates the transcri ption of Phase II detoxifying enzymes through the ARE, To explore the upstream signaling pathways leading to gene expression, we studied the involvement of the mitogen-activated protein kinases (MAPKs) extracel lular signal-regulated kinase 2 (ERK2) and c-Jun N-terminal kinase 1 ( JNK1), Potent activation of ERK2 was seen following treatment of HepG2 cells with different concentrations of GTP, Similar to ERK2, JNK1 was also strongly activated by treatment with GTP, although to a lesser e xtent and in a different dose-dependent fashion, Kinetic studies revea led that GTP activation of JNK1 was delayed and sustained, whereas ERK 2 activation was rapid and transient, Furthermore, GTP treatment also increased mRNA levels of the immediate-early genes c-jun and c-fos, as determined by reverse transcriptase-coupled polymerase chain reaction , Taken together, these studies provide insights into the action of GT P and suggest that the stimulation MAPKs may be the potential signalin g pathways utilized by GTP to activate ARE-dependent genes.