Involvement of nuclear factor kappaB in up-regulation of aldose reductase gene expression by 12-O-tetradecanoylphorbol-13-acetate in HeLa cells.
To elucidate the molecular mechanisms underlying the up-regulation of aldose reductase observed in many cancer cells, we investigated the signal transduction pathways mediating induction of aldose reductase gene expression by 12-O-tetradecanoylphorbol-13-acetate, a potent tumor promoter. A maximum of four-fold induction in aldose reductase mRNA was demonstrated in HeLa cells treated with 12-O-tetradecanoylphorbol-13-acetate. The increased level of aldose reductase transcript was accompanied by the elevated level of enzyme activity, and completely abolished in the presence of actinomycin D. Inhibitors of protein kinase C, bisindolylmaleimide I and calphostin C, as well as inhibitors of tyrosine kinase, genistein and tyrphostin A23, significantly attenuated 12-O-tetradecanoylphorbol-13-acetate-induced increase in aldose reductase mRNA. Blockade of the p38 mitogen-activated protein kinase pathway by SB203580 also suppressed 12-O-tetradecanoylphorbol-13-acetate-induced aldose reductase expression. The promoter activity of aldose reductase gene was significantly augmented in the cells treated with 12-O-tetradecanoylphorbol-13-acetate, but attenuated in the presence of bisindolylmaleimide I, tyrphostin A23 or SB203580. Pyrrolidinedithiocarbamate, a nuclear factor kappaB inhibitor, dose-dependently suppressed 12-O-tetradecanoylphorbol-13-acetate-induced increase in aldose reductase mRNA. 12-O-tetradecanoylphorbol-13-acetate augmented the DNA binding activity of nuclear factor kappaB and nuclear factor kappaB-dependent gene transcription, and these effects were attenuated by bisindolylmaleimide I or tyrphostin A23, but not by SB203580. Taken together, activation of protein kinase C and tyrosine kinase by 12-O-tetradecanoylphorbol-13-acetate elicits increased promoter activity of aldose reductase gene via nuclear factor kappaB. A p38 mitogen-activated protein kinase pathway, distinct from the tyrosine kinase pathway, may also take part in 12-O-tetradecanoylphorbol-13-acetate-induced increase in aldose reductase gene expression.
Lee
Young Sook
YS
Department of Pharmacology, Gyeongsang Institute of Health Science, College of Medicine, Gyeongsang National University, 92 Chilam-Dong, Jinju 660-751, Republic of Korea.
Paek
Kyung Shin
KS
Kang
Eun Sil
ES
Jang
Han-su
HS
Kim
Hyo Jung
HJ
Kang
Young Jin
YJ
Kim
Jin-Hoi
JH
Lee
Hoon Taek
HT
Lee
Jae Heun
JH
Chang
Ki Churl
KC
Nishinaka
Toru
T
Seo
Han Geuk
HG
D000449:Aldehyde Reductase / Q000235:genetics* / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002273:Carcinogens; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D003513:Cycloheximide; D000449:Aldehyde Reductase; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate