Decisive role of apurinic/apyrimidinic endonuclease/Ref-1 in initiation of cell death.
The apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE/Ref-1) is involved in the base excision repair of apurinic/apyrimidinic sites induced by oxidative DNA damage. APE/Ref-1 was decreased by kainic acid (KA) injury in a time-dependent manner at the level of proteins, not transcripts. We investigated whether alteration of APE/Ref-1 amounts would influence hippocampal cell fate, survival or death, after KA injury. Overexpression of APE/Ref-1 using adenovirus and restoration of APE small peptides significantly reduced KA-induced hippocampal cell death. Both silencing of APE/Ref-1 by siRNA and inhibition of endonuclease by an antibody significantly increased caspase-3 activity and apoptotic cell death triggered from the early time after exposure to KA. These findings suggest that cell death is initiated by reducing APE/Ref-1 protein and inhibiting its repair function in spite of enough protein amounts. In conclusion, APE/Ref-1 may be a regulator of cell death initiation, and APE small peptides could provide molecular mechanism-based therapies for neuroprotection in progressive excitotoxic neuronal damage.
Cho
Kyoung Joo
KJ
Department of Neurology, Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, 134, Sinchon-dong, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
Kim
Hyun Jeong
HJ
Park
Soo Chul
SC
Kim
Hyun Woo
HW
Kim
Gyung Whan
GW
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
D010455:Peptides; D034741:RNA, Small Interfering; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D007608:Kainic Acid