Thapsigargin has similar effect on p53 protein response to benzo[a]pyrene-DNA adducts as TPA in mouse skin.
The level of p53 tumor suppressor protein increases in response to DNA damage caused by benzo[a]pyrene (B[a]P). The most used tumor promoter in the two step mouse skin carcinogenesis model, 12-O-tetradecanoylphorbol-13-acetate (TPA) decreases this response in mouse skin. In this study the effect of another promoter, thapsigargin was tested on B[a]P-induced p53 response using immunohistochemistry, western blotting and immunoelectron microscopy. We also studied the localization of p53 protein after treatments with BP and TPA or thapsigargin. Thapsigargin had a TPA-like effect on the acute induction of p53 protein related to benzo[a]pyrene-7, 8-diol-9,10-epoxide-DNA adducts in the skin of C57BL/6 mouse. After B[a]P treatment, there was slightly more putatively wild-type p53 protein in nuclei than in cytoplasm of the cells. Neither TPA nor thapsigargin affected the localization of p53 protein. Since both compounds increase the level of intracellular calcium, the inhibition of the p53 response may depend on the level of intracellular calcium. Inhibition of the putatively genome-protecting increase in p53 protein may be one of the critical effects of tumor promoters.
Serpi
R
R
Department of Pharmacology and Toxicology, University of Oulu,PO Box 5000, FIN-90401 Oulu and Department of Biology,University of Oulu, PO Box 333, FIN-90571 Oulu, Finland.
Piispala
J
J
Järvilehto
M
M
Vähäkangas
K
K
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000032:analysis*; D000096:Acetone; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D018736:DNA Adducts / Q000032:analysis*; D004249:DNA Damage; D003864:Depression, Chemical; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016158:Genes, p53; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism; D015388:Organelles / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
D002273:Carcinogens; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; D000096:Acetone; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D019284:Thapsigargin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium