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 F2 alpha (PGF2 alpha) 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 (Kd) or number of PGF2 alpha receptors. Inhibition of PG synthesis was without effect upon desensitization, demonstrating that the effect was not agonist-induced. Desensitization 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.
Black
F M
FM
Department of Biochemistry, University of Glasgow, Scotland, U.K.
Wakelam
M J
MJ
D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004075:Diglycerides / Q000032:analysis; D015237:Dinoprost / Q000494:pharmacology*; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras; D007295:Inositol Phosphates / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology
D004075:Diglycerides; D007295:Inositol Phosphates; D015237:Dinoprost; D011493:Protein Kinase C