Fritz G, Kaina B
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, Mainz, D-55131, Germany.
Biochem Biophys Res Commun. 2000 Feb 24;268(3):784-9. doi: 10.1006/bbrc.2000.2211.
rhoB encoding a Ras-related GTPase is immediate-early inducible by genotoxic treatments. To address the question of the physiological role of RhoB in cellular defense, cells stably overexpressing wild-type RhoB protein were generated. Overexpression of RhoB renders cells hypersensitive to the killing effect of alkylating agents including antineoplastic drugs but not to UV-light and doxorubicin. As compared to control cells, RhoB overexpressing cells revealed an increase in the frequency of alkylation-induced apoptotic cell death. This indicates that RhoB is involved in modulating apoptotic signaling. Furthermore, overexpression of RhoB resulted in a prolonged transient block to DNA replication upon MMS treatment. UV-induced replication blockage was not affected by RhoB. Based on the data we suggest RhoB to be a novel regulatory factor which takes influence on the level of cytotoxicity of DNA damaging drugs and forces cells to alkylation-induced apoptosis. The data indicate that this might be due to RhoB mediated delay in cell cycle progression upon alkylation treatment.
编码一种与Ras相关的GTP酶的rhoB可被基因毒性处理快速早期诱导。为了解决RhoB在细胞防御中的生理作用问题，构建了稳定过表达野生型RhoB蛋白的细胞。RhoB的过表达使细胞对包括抗肿瘤药物在内的烷化剂的杀伤作用高度敏感，但对紫外线和阿霉素不敏感。与对照细胞相比，过表达RhoB的细胞显示出烷化诱导的凋亡性细胞死亡频率增加。这表明RhoB参与调节凋亡信号传导。此外，RhoB的过表达导致在MMS处理后对DNA复制的短暂阻断延长。紫外线诱导的复制阻断不受RhoB影响。基于这些数据，我们认为RhoB是一种新型调节因子，它影响DNA损伤药物的细胞毒性水平，并迫使细胞发生烷化诱导的凋亡。数据表明，这可能是由于RhoB介导的烷化处理后细胞周期进程延迟所致。
