Enhancing effect of tumor promoters, phorbol esters and teleocidins on nuclear receptor-mediated transcription.
Interaction between a tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), and ligands of nuclear receptors has been interpreted as the result of crosstalk between the nuclear receptors and oncogenic transcription factor AP-1. We examined the effects of various tumor promoters on transcription mediated by several nuclear receptors (RAR, TR, and ROR) by using thymidine kinase promoter-based reporter systems. TPA-type and other types of tumor promoters (okadaic acid, thapsigargin) enhanced reporter gene transcription independently of the cognate ligands for the receptors. Various kinds of TPA-type tumor promoters, teleocidine and its synthetic derivatives (indolactam, benzolactams) enhanced reporter gene transcription in proportion to their differentiation-inducing activities. Although TPA is known to activate protein kinase C (PKC), some PKC inhibitors did not inhibit the effect of TPA on reporter gene transcription. Interestingly, staurosporin, a strong PKC inhibitor and also a tumor promoter, enhanced the effect of TPA and weakly enhanced the reporter transcription itself. These results suggest this reporter system is useful for the evaluation of effects on the gene expression of various tumor promoters, including non-TPA type.
Fukasawa
H
H
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan. fukasawa@mol.f.u-tokyo.ac.jp
Yamaguchi
M
M
Hashimoto
Y
Y
Endo
Y
Y
Shudo
K
K
D000818:Animals; D019556:COS Cells; D002273:Carcinogens / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007769:Lactams / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008235:Lyngbya Toxins / Q000494:pharmacology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D019319:Okadaic Acid / Q000494:pharmacology; D010957:Plasmids; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014162:Transfection
D002273:Carcinogens; D007211:Indoles; D007769:Lactams; D008235:Lyngbya Toxins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C000607071:RARA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; C113786:benzolactam V8-310; D019319:Okadaic Acid; C022176:teleocidins; D019284:Thapsigargin; C043969:indolactam V; D008156:Luciferases; D013937:Thymidine Kinase; D013755:Tetradecanoylphorbol Acetate