DESENSITIZATION OF PROSTAGLANDIN-F2-ALPHA-STIMULATED INOSITOL PHOSPHATE GENERATION IN NIH-3T3 FIBROBLASTS TRANSFORMED BY OVEREXPRESSION OF NORMAL C-HA-RAS-1, C-KI-RAS-2 AND C-N-RAS GENES

The stimulation of inositol phosphate generation in control and ras-gene-transformed NIH-3T3 cells by prostaglandin F(2α) (PGF(2α)) was investigated. Compared with the control cells, a desensitization of the response was observed in cells transformed by the overexpression of N-, Ha-, or Ki-ras genes. This desensitization was without effect upon the concentration causing half-maximal effect (EC50), dissociation constant (K(d)) or number of PGF(2α) receptors. Inhibition of PG synthesis was without effect upon desensitization, demsonstrating that the effect was not agonist-induced. Desensitizations could be induced in NIH-3T3 cells by culturing under conditions where the cells were all in the exponential growth phase, or by a 12 h exposure to a C-kinase-activating phorbol ester. These results suggest that desensitization of certain agonist-induced inositol phospholipid responses in ras-transformed cells is a consequence of increased cell proliferation and associated amplification in C-kinase activity and is an indirect consequence of transformation by ras.