Expression of death receptor 4 induces caspase-independent cell death in MMS-treated yeast.
DR4, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, is a key element in the extrinsic pathway of TRAIL/TRAIL receptor-related apoptosis that exerts a preferential toxic effect against tumor cells. However, TRAIL and DR4 are expressed in various normal cells, and recent studies indicate that DR4 has a number of non-apoptotic functions. In this study, we evaluated the effects of human DR4 expression in yeast to determine the function of DR4 in normal cells. The expression of DR4 in yeast caused G1 arrest, which resulted in transient growth inhibition. Moreover, treatment of DR4-expressing yeast with a DNA damaging agent, MMS, elicited drastic, and sustained cell growth inhibition accompanied with massive apoptotic cell death. Further analysis revealed that cell death in the presence of DNA damage and DR4 expression was not dependent on the yeast caspase, YCA1. Taken together, these results indicate that DR4 triggers caspase-independent programmed cell death during the response of normal cells to DNA damage.
Kang
Mi-Sun
MS
Department of Pharmacology, Inha Research Institute for Medical Sciences, Incheon 400-712, Republic of Korea.
Lee
Sung-Keun
SK
Park
Chang-Shin
CS
Kang
Ju-Hee
JH
Bae
Sung-Ho
SH
Yu
Sung-Lim
SL
D017209:Apoptosis; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D017353:Gene Deletion; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D009153:Mutagens; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D029701:Saccharomyces cerevisiae Proteins; C105190:TNFRSF10A protein, human; D008741:Methyl Methanesulfonate; D020169:Caspases; C456272:MCA1 protein, S cerevisiae