RhoB controls the 24 kDa FGF-2-induced radioresistance in HeLa cells by preventing post-mitotic cell death
RhoB controls the 24 kDa FGF-2-induced radioresistance in HeLa cells by preventing post-mitotic cell death
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DOI：
10.1038/sj.onc.1205746
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发表时间：
2002-09-05
期刊：
影响因子：
8
通讯作者：
Favre, G
中科院分区：
文献类型：
--
作者：
Ader, I;Toulas, C;Favre, G
法尼基化Ras癌蛋白诱导细胞对电离辐射的抵抗，这种抵抗可以通过法尼基转移酶抑制剂（FTI）逆转。我们之前证明，在携带ras的野生型HeLa细胞中表达24 kDa FGF2亚型，诱导辐射抗性，FTI也能逆转这种抗性。我们验证了野生型Ras或RhoB（已被提出作为潜在的FTI靶点）可以控制fgf -2诱导的辐射抵抗机制的假设。为此，我们在24 kDa FGF2转染的HeLa细胞中表达了Ras （RasN17）和Rho （RhoBN19）的诱导显性阴性形式，并分析了它们在辐照后的存活情况。虽然RasN17诱导后未观察到细胞存活改变，但RhoBN19的表达诱导了FGF2耐辐射HeLa细胞的放射增敏，其范围与特异性FTI R115777处理48小时后观察到的范围相同。此外，我们发现激活RhoB而不是RhoA诱导NIH3T3细胞的辐射抗性。RhoBN19表达的放射增敏作用是由于诱导辐射诱导的有丝分裂后细胞死亡。综上所述，这些数据表明，24 kDa fgf -2诱导的辐射抗性是由Rho通路控制的，并且表明RhoB应该是细胞对电离辐射抗性的主要决定因素。
Farnesylated Ras oncoprotein induces a cellular resistance to ionizing radiation that can be reversed by farnesyltransferase inhibitors (FTI). We previously demonstrated that, expression of the 24 kDa FGF2 isoform in wild type ras bearing HeLa cells, induced radioresistance which was also reversed by FTI. We tested the hypothesis that wild type Ras or RhoB, which has been proposed as a potential FTI target, could control the FGF-2-induced radioresistance mechanisms. For this, we expressed inducible dominant negative forms of Ras (RasN17) and Rho (RhoBN19) in 24 kDa FGF2 transfected HeLa cells and analysed their survival after irradiation. While no cell survival modification was observed after RasN17 induction, the expression of RhoBN19 induced a radiosensitization of FGF2 radioresistant HeLa cells in the same range as the one observed after a 48 h treatment with the specific FTI, R115777. Moreover, we showed that activated RhoB but not RhoA induced radioresistance in NIH3T3 cells. The radiosensitizer effect of RhoBN19 expression was due to the induction of the radiation induced post-mitotic cell death. Taken together, these data demonstrate that 24 kDa FGF-2-induced radioresistance is controlled by Rho pathways and suggest that RhoB should be a major determinant in cellular resistance to ionizing radiation.