Expression of phosphoinositide-specific phospholipase C (PLC)-gamma during the retinoic acid (RA)-induced differentiation of F9 teratocarcinoma stem cells was investigated. PLC-gamma activity and PLC-gamma protein content were decreased during the differentiation of F9 teratocarcinoma stem cells induced by a combination (RACT) of RA, dibutyryl cyclic AMP (C) and theophylline (T). However, PLC-gamma activity and protein levels in RA- or C- and T-treated F9 cells remained the same as that of the F9 stem cells. Northern analysis of the 5.4-kb PLC-gamma transcript in differentiated F9 cells by RACT revealed that RACT decreased the PLC-gamma gene expression. These results suggest that the expression of PLC-gamma is negatively controlled by RACT treatment in the differentiation of F9 teratocarcinoma stem cells.