title: Enhanced induction of epidermal ornithine decarboxylase activity in C57BL/6 compared to DBA/2 mice by protein kinase C-activating skin tumor promoters: relevance to genetically mediated differences in promotion susceptibility.
abstract: Previous work from our laboratory demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) or a synthetic diacylglycerol induced significantly higher epidermal ornithine decarboxylase (ODC) activity in C57BL/6 than in DBA/2 mice. To understand further the genetic basis for this strain difference, two tumor promoters were evaluated for their effects on epidermal ODC activity: teleocidin, which activates protein kinase C (PKC); and 1,8-dihydroxyl-3-methyl-9-anthrone (chrysarobin), which does not. In addition, the ODC induction response in B6D2F1 offspring and BXD recombinant inbred (RI) strains was examined following multiple treatments with TPA. A single topical application of teleocidin to mouse dorsal skin led to the hyperinduction of epidermal ODC activity in C57BL/6 mice. In contrast, while chrysarobin induced epidermal ODC activity, no significant differences in the magnitude of this response were observed in SENCAR, DBA/2 or C57BL/6 mice. Consistent with our previous findings, the magnitude of ODC induction by teleocidin in these three mouse lines (C57BL/6 greater than SENCAR greater than DBA/2) did not correlate with their susceptibility to tumor promotion by TPA (SENCAR greater than DBA/2 greater than C57BL/6). ODC activity induced by multiple application of TPA in B6DF1 mice, whose susceptibility to phorbol ester tumor promotion is inherited as an incomplete dominant trait, was comparable to that induced in C57BL/6 mice at all the doses examined. Cluster analysis of TPA-induced ODC activity in BXD RI strains allowed us tentatively to group them into four or five phenotypes and to estimate a minimum of two genetic loci controlling TPA-induced ODC activity. Furthermore, in BXD RI strains, there was no apparent relationship between the magnitude of ODC induction and responsiveness to tumor promotion or sustained hyperplasia. Collectively, these results suggest that hyperinducibility of ODC in response to PKC-activating tumor promoters is inherited as an autosomal dominant trait, and that genetic determinants for ODC induction, at least in C57BL/6 and DBA/2 mice, appear completely independent of those controlling tumor promotion susceptibility.
authors.affiliation: Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957.
authors.forename: A
authors.initials: A
authors.lastname: Imamoto
authors.forename: L M
authors.initials: LM
authors.lastname: Beltrán
authors.forename: H
authors.initials: H
authors.lastname: Fujiki
authors.forename: K J
authors.initials: KJ
authors.lastname: Chenicek
authors.forename: J
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D000818:Animals; D000873:Anthracenes; D002273:Carcinogens; D016000:Cluster Analysis; D004198:Disease Susceptibility / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease; D008235:Lyngbya Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000201:enzymology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000873:Anthracenes; D002273:Carcinogens; D008235:Lyngbya Toxins; C022176:teleocidins; C013883:chrysarobin; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate