Opposing effects of a ras oncogene on growth factor-stimulated phosphoinositide hydrolysis: desensitization to platelet-derived growth factor and enhanced sensitivity to bradykinin.
Opposing effects of a ras oncogene on growth factor-stimulated phosphoinositide hydrolysis: desensitization to platelet-derived growth factor and enhanced sensitivity to bradykinin.
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ras 癌基因对生长因子刺激的磷酸肌醇水解的相反作用：对血小板衍生生长因子的脱敏和对缓激肽的敏感性增强。
DOI：
10.1073/pnas.84.9.2648
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发表时间：
1987
影响因子：
11.1
通讯作者：
Racker,E
中科院分区：
文献类型：
--
作者：
Parries,G;Hoebel,R;Racker,E
转化的Harvey或Kirsten ras基因的表达对血小板衍生生长因子(PDGF)和缓激肽激活磷脂酶C介导的肌醇磷脂水解酶的能力产生了相反的影响。在[~3H]肌醇标记的大鼠成纤维细胞中，PDGF(5 ng/ml)作用2分钟后使[~H]肌醇三磷酸(InsP3)水平增加2倍，在LiCl存在时，使[~3H]肌醇一磷酸(InsP_1)水平在30分钟后增加3~8倍。然而，在EJ-ras转基因的大鼠-1细胞中，PDGF受体的水平接近正常，PDGF导致[~3H]InsP3或[~3H]InsP1很少或没有积聚。同样，在NIH3T3细胞和v-src转化的3T3细胞中也观察到了PDGF的显著刺激作用，但在Kirsten肉瘤病毒转化的3T3细胞和v-Ha-ras DNA转染组中未观察到明显的刺激作用。Ras转化细胞中这种磷脂酰肌醇反应的减弱与对PDGF的促有丝分裂反应显著减弱有关。另一方面，血清对ras转化成纤维细胞的肌醇磷脂代谢和DNA合成均有数倍的刺激作用。在携带糖皮质激素诱导的v-Ha-ras基因的NIH3T3细胞中，p21ras的表达与PDGF刺激的[~3H]InsP1积聚的丧失密切相关。与ras诱导的对PDGF的脱敏相反，ras转化的NIH3T3细胞对缓激肽的敏感性增强；这一效应与高亲和力[~3H]缓激肽结合水平的升高有关。我们认为ras基因产物(P21)可以通过改变特定的生长因子受体的性质，直接或间接地影响生长因子刺激的肌醇磷脂的水解和DNA的合成。
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.