Diacylglycerol is an effector of the clonal expansion of cells containing activated Ha-ras genes.
Diacylglycerols (DAG) are lipid second messengers which are generated during phospholipase-catalyzed hydrolysis of phospholipids. The model DAG, sn-1,2-didecanoylglycerol (DIC10), is an effective topical tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. We now report that 11/12 of DMBA-initiated/DIC10-promoted papillomas examined contain an A-->T mutation in the 61st codon of the Ha-ras gene, suggesting that DAGs affect the clonal expansion of activated Ha-ras-containing cells. To explore further the DIC10-induced clonal expansion of activated Ha-ras-containing cells, we have examined the tumor-promoting effect of DIC10 in the skin of transgenic TG.AC mice, which harbor a v-Ha-ras transgene. By 9 weeks of promotion, 100% of the TG.AC mice developed squamous papillomas and by 15 weeks these mice developed > 20 papillomas/mouse. Because fatty acids are known to participate in signal transduction pathways, and since cellular lipases could cleave the fatty acid side chains present in DIC10, we have examined the tumor promoting activity of n-decanoic acid to verify the specificity of promotional activity of DIC10. n-Decanoic acid did not function as a tumor promoter. These data implicate DAG as an effector of the clonal expansion of mutated Ha-ras-containing cells, and support a mechanism whereby an increase in endogenous DAG could contribute to the clonal expansion of cells containing a Ha-ras oncogene.
Mills
K J
KJ
Department of Toxicology, North Carolina State University, Raleigh 27695-7633.
Reynolds
S H
SH
Smart
R C
RC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000225:Adenine; D000818:Animals; D001483:Base Sequence; D002999:Clone Cells; D003652:Decanoic Acids / Q000494:pharmacology; D004075:Diglycerides / Q000502:physiology*; D011905:Genes, ras; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D015290:Second Messenger Systems; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate; D013941:Thymine
D003652:Decanoic Acids; D004075:Diglycerides; D009838:Oligodeoxyribonucleotides; C044297:1,2-didecanoylglycerol; C031071:decanoic acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D000225:Adenine; D013755:Tetradecanoylphorbol Acetate; D013941:Thymine