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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Elevated small GTPase activation influences the cell proliferation signaling control in Niemann–Pick type C fibroblasts
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Elevated small GTPase activation influences the cell proliferation signaling control in Niemann–Pick type C fibroblasts

机译：GTPase活化水平升高会影响Niemann–Pick C型成纤维细胞的细胞增殖信号控制

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摘要

Niemann–Pick type C (NPC) disease is characterized at the cellular level by the intracellular accumulation of free cholesterol. We have previously identified a similar phenotype in cystic fibrosis (CF) cell models that results in the activation of the small GTPase RhoA. The hypothesis of this study was that NPC cells would also exhibit an increase in small GTPase activation. An examination of the active, GTP-bound form of GTPases revealed a basal increase in the content of the active-form Ras and RhoA small GTPases in NPC fibroblasts compared to wt controls. To assess whether this increase in GTP-bound Ras and RhoA manifests a functional outcome, the expression of the proliferation control proteins p21/waf1 and cyclin D were examined. Consistent with increased GTPase signaling, p21/waf1 expression is reduced and cyclin D expression is elevated in NPC fibroblasts. Interestingly, cell growth rate is not altered in NPC fibroblasts compared to wt cells. However, NPC sensitivity to statin treatment is reversed by addition of the isoprenoid geranylgeranyl pyrophosphate (GGPP), a modifier of RhoA. It is concluded that Ras and RhoA basal activation is elevated in NPC fibroblasts and has an impact on cell survival pathways.
机译：尼曼-匹克C型（NPC）疾病在细胞水平上以游离胆固醇的细胞内积累为特征。我们先前已经在囊性纤维化（CF）细胞模型中发现了一个类似的表型，该表型导致了小GTPase RhoA的激活。这项研究的假设是，NPC细胞在小GTP酶激活方面也将表现出增加。对活性，GTP结合形式的GTPases的检查显示，与wt对照相比，NPC成纤维细胞中活性形式的Ras和RhoA小GTPases的含量基本增加。为了评估与GTP结合的Ras和RhoA的这种增加是否表现出功能性结果，检查了增殖控制蛋白p21 / waf1和细胞周期蛋白D的表达。与增加的GTPase信号转导一致，在NPC成纤维细胞中p21 / waf1表达降低，而cyclin D表达升高。有趣的是，与wt细胞相比，NPC成纤维细胞的细胞生长速率没有改变。但是，NPC对他汀类药物治疗的敏感性可通过添加RhoA的异戊二烯类香叶基香叶基焦磷酸酯（GGPP）来逆转。结论是，RPC和RhoA的基础活化在NPC成纤维细胞中升高，并且对细胞存活途径有影响。

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