Facilitation of DNA damage-induced apoptosis by endoplasmic reticulum protein mitsugumin23.
The endoplasmic reticulum (ER) emanates context-dependent signals, thereby mediating cellular response to a variety of stresses. However, the underlying molecular mechanisms have been enigmatic. To better understand the signaling capacity of the ER, we focused on roles played by mitsugumin23 (MG23), a protein residing predominantly in this organelle. Overexpression of MG23 in human embryonic kidney 293T cells specifically enhanced apoptosis triggered by etoposide, a DNA-damaging anti-cancer drug. Conversely, genetic deletion of MG23 reduced susceptibility of thymocytes to DNA damage-induced apoptosis, which was demonstrated by whole-body irradiation experiments. In this setting, induction of the tumor-suppressor gene p53 was attenuated in MG23-knockout thymocytes as compared with their wild-type counterparts, consistent with the elevated radioresistance. It is therefore suggested that MG23 is an essential component of ER-generated lethal signals provoked upon DNA damage, specifying cell fate under pathophysiological conditions.
Yamazaki
Tetsuo
T
Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. yamazakt@ph.tokushima-u.ac.jp
Sasaki
Nozomi
N
Nishi
Miyuki
M
Takeshima
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D055786:Gene Knockout Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011836:Radiation Tolerance / Q000235:genetics; D013312:Stress, Physiological; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; C547817:mitsugumin23 protein, human; C547818:mitsugumin23 protein, mouse; D005047:Etoposide