Ras-related GTPase RhoB forces alkylation-induced apoptotic cell death.
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.
Fritz
G
G
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, Mainz, D-55131, Germany. fritz@mail.uni-mainz.de
Kaina
B
B
D016475:3T3 Cells; D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D051381:Rats; D014162:Transfection; D014466:Ultraviolet Rays; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
D018906:Antineoplastic Agents, Alkylating; D018076:DNA, Complementary; D008741:Methyl Methanesulfonate; D020743:rhoB GTP-Binding Protein