Opposing effects of a ras oncogene on growth factor-stimulated phosphoinositide hydrolysis: desensitization to platelet-derived growth factor and enhanced sensitivity to bradykinin.
Expression of a transforming Harvey or Kirsten ras gene caused opposing effects in the ability of platelet-derived growth factor (PDGF) and bradykinin to activate phospholipase C-mediated phosphoinositide hydrolysis. In [3H]inositol-labeled rat-1 fibroblasts, PDGF (5 ng/ml) resulted in a 2-fold increase in the level of [3H]inositol trisphosphate (InsP3) after 2 min and, in the presence of LiCl, a 3- to 8-fold increase in the level of [3H]inositol monophosphate (InsP1) after 30 min. However, in EJ-ras-transfected rat-1 cells, which exhibit near normal levels of PDGF receptors, PDGF resulted in little or no accumulation of either [3H]InsP3 or [3H]InsP1. Similarly, marked stimulations by PDGF were observed in NIH 3T3 cells, as well as in v-src-transformed 3T3 cells, but not in 3T3 cells transformed by Kirsten sarcoma virus or by transfection with v-Ha-ras DNA. This diminished phosphoinositide response in ras-transformed cells was associated with a markedly attenuated mitogenic response to PDGF. On the other hand, both phosphoinositide metabolism and DNA synthesis in ras-transformed fibroblasts were stimulated several-fold by serum. In NIH 3T3 cells carrying a glucocorticoid-inducible v-Ha-ras gene, a close correlation was found between the expression of p21ras and the loss of PDGF-stimulated [3H]InsP1 accumulation. In contrast to this ras-induced desensitization to PDGF, ras-transformed NIH 3T3 cells exhibited an enhanced sensitivity to bradykinin; this effect was associated with an elevated level of high-affinity [3H]bradykinin binding. We propose that a ras gene product (p21) can, directly or indirectly, influence growth factor-stimulated phosphoinositide hydrolysis, as well as DNA synthesis, via alterations in the properties of specific growth factor receptors.
D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D009857:Oncogenes; D010716:Phosphatidylinositols / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018002:Receptors, Bradykinin; D011956:Receptors, Cell Surface / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D010982:Platelet-Derived Growth Factor; D018002:Receptors, Bradykinin; D011956:Receptors, Cell Surface; D017981:Receptors, Neurotransmitter; D015544:Inositol 1,4,5-Trisphosphate; D017479:Receptors, Platelet-Derived Growth Factor; D001920:Bradykinin