Enhanced sensitivity to apoptosis in Ras-transformed thyroid cells.
Enhanced sensitivity to apoptosis in Ras-transformed thyroid cells.
复制标题
Ras 转化的甲状腺细胞对细胞凋亡的敏感性增强。
DOI：
10.1038/sj.onc.1204928
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Meinkoth,JL
中科院分区：
文献类型：
--
作者：
Cheng,G;Meinkoth,JL
Ras突变在甲状腺癌中发生频率很高。在体外，Ras在甲状腺细胞中的作用是多效性的，因为已报道激活的Ras的表达刺激增殖和凋亡。了解Ras转化细胞的存活与死亡的因素对于我们理解Ras对甲状腺肿瘤和其他癌症的贡献至关重要。组成型表达致癌H-Ras致敏Wistar大鼠甲状腺（WRT）细胞凋亡刺激的多重侮辱。当被剥夺的基质附着，Ras转化细胞死亡的凋亡细胞死亡的频率很高。相比之下，亲本细胞对悬浮诱导的细胞死亡更具抗性。Ras对锚定非依赖性细胞死亡的影响是由选择性地向Raf-1发出信号的突变蛋白复制的，而不是由优先结合RalGDS的突变Ras复制的。选择性激活PI 3 K的Ras突变体的表达导致了对凋亡诱导的细胞死亡的实质性保护。MAPK活性增加，在粘附Ras 12 V和Ras 12 V35 S表达细胞，但取消后脱离。有趣的是，受损的MAPK活性足以刺激粘附Ras转化细胞的凋亡，但在亲本细胞中不。用PI 3 K抑制剂治疗也选择性地刺激Ras转化细胞的凋亡。这些结果表明，激活的Ras的组成型表达对甲状腺细胞的存活具有不同的影响。此外，Ras表达导致甲状腺细胞对MAPK和PI 3 K活性的更大依赖性以使其存活。
Ras mutations occur at high frequency in thyroid cancer. In vitro, the effects of Ras in thyroid cells are pleiotropic in that expression of activated Ras has been reported to stimulate proliferation and apoptosis. An understanding of the factors that contribute to the survival versus demise of Ras-transformed cells is essential to our understanding of the contribution of Ras to thyroid neoplasia and other cancers. Constitutive expression of oncogenic H-Ras sensitized Wistar rat thyroid (WRT) cells to apoptosis stimulated by multiple insults. When deprived of matrix attachment, Ras-transformed cells perished by apoptotic cell death at a high frequency. In contrast, parental cells were more resistant to suspension-induced cell death. Ras effects on anchorage-independent cell death were reproduced by a mutant protein that signals selectively to Raf-1, but not by mutant Ras that preferentially binds to RalGDS. Expression of a Ras mutant that selectively activates PI3K resulted in substantial protection from detachment-induced cell death. MAPK activity was increased in adherent Ras12V-and Ras12V35S-expressing cells, but abolished upon detachment. Interestingly, impaired MAPK activity was sufficient to stimulate apoptosis in adherent Ras-transformed cells, but not in parental cells. Treatment with a PI3K inhibitor also stimulated apoptosis selectively in Ras-transformed cells. These results demonstrate that constitutive expression of activated Ras elicits differential effects on the survival of thyroid cells. Moreover, Ras expression results in a greater dependence of thyroid cells on MAPK and PI3K activity for their survival.