Induction of thioredoxin, thioredoxin reductase and glutaredoxin activity in mouse skin by TPA, a calcium ionophore and other tumor promoters.
We have measured the levels of thioredoxin, thioredoxin reductase and glutaredoxin enzyme activity in mouse skin following topical application of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator and tumor promoter. The specific activity of thioredoxin and thioredoxin reductase in extracts from normal epidermis increased by 40 and 50%, respectively, after single or multiple application of TPA. Multiple applications (twice per week for 2 weeks) of TPA increased glutaredoxin activity by >300%. Induction of the proteins lasted several days. Other PKC activators, like 12-O-retinoylphorbol 13-acetate, mezerein, 1-oleoyl-2-acetylglycerol and the calcium ionophore A23187, also induced all the enzyme activities. Phorbol and 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate, weak activators of PKC, selectively induced the thioredoxin system only and did not influence glutaredoxin activity. Multiple applications of TPA to tumor initiated (7,12-dimethyl[a]benzanthracene-treated) skin resulted in elevated levels of both the thioredoxin and glutaredoxin systems when examined 6 days after the last phorbol ester treatment. Induction of thioredoxin, thioredoxin reductase and glutaredoxin activities by TPA and calcium ionophores may play a general role in the epigenetic mechanism of tumor promotion via thiol redox control mechanisms.
Kumar
S
S
Department of Medical Biochemistry and Biophysics, Medical Nobel Institute for Biochemistry, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Holmgren
A
A
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology*; D003043:Cocarcinogenesis; D004075:Diglycerides / Q000494:pharmacology; D004224:Diterpenes; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005446:Fluocinolone Acetonide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D054477:Glutaredoxins; D005978:Glutathione / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology*; D051379:Mice; D010084:Oxidation-Reduction; D010088:Oxidoreductases; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000096:biosynthesis* / Q000235:genetics; D013879:Thioredoxins / Q000378:metabolism*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
D002273:Carcinogens; D004075:Diglycerides; D004224:Diterpenes; D054477:Glutaredoxins; D007476:Ionophores; D010703:Phorbol Esters; D011506:Proteins; D013729:Terpenes; D005446:Fluocinolone Acetonide; C011309:mezerein; D000001:Calcimycin; D014108:Tosylphenylalanyl Chloromethyl Ketone; D013879:Thioredoxins; D014212:Tretinoin; D015127:9,10-Dimethyl-1,2-benzanthracene; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; C032974:12-O-retinoylphorbol-13-acetate; C038237:1-oleoyl-2-acetylglycerol; D010088:Oxidoreductases; D013880:Thioredoxin-Disulfide Reductase; D011493:Protein Kinase C; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium