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 exp ansion of activated Ha-ras-containing cells, we have examined the tumo r-promoting effect of DIC10 in tale skin of transgenic TG.AC mice, whi ch harbor a v-Ha-ras transgene. By 9 weeks of promotion, 100% of the T G.AC mice developed squamous papillomas and by 15 weeks these mice dev eloped >20 papillomas/mouse. Because fatty acids are known to particip ate in signal transduction pathways, and since cellular lipases could cleave the fatty acid side chains present in DIC10, we have examined t he tumor promoting activity of n-decanoic acid to verify the specifici ty of promotional activity of DIC10. n-Decanoic acid did not function as a tumor promoter. These data implicate BAG as an effector of the cl onal expansion of mutated Ha-ras-containing cells, and support a mecha nism whereby an increase in endogenous BAG could contribute to the clo nal: expansion of cells containing a Ha-ras oncogene.