Repeated electroconvulsive seizure induces c-Myc down-regulation and Bad inactivation in the rat frontal cortex.
Repeated electroconvulsive seizure (ECS), a model for electroconvulsive therapy (ECT), exerts neuroprotective and proliferative effects in the brain. This trophic action of ECS requires inhibition of apoptotic activity, in addition to activation of survival signals. c-Myc plays an important role in apoptosis of neurons, in cooperation with the Bcl-2 family proteins, and its activity and stability are regulated by phosphorylation and ubiquitination. We examined c-Myc and related proteins responsible for apoptosis after repeated ECS. In the rat frontal cortex, repeated ECS for 10 days reduced the total amount of c-Myc, while increasing phosphorylation of c-Myc at Thr58, which reportedly induces degradation of c-Myc. As expected, ubiquitination of both phosphorylated and total c-Myc increased after 10 days ECS, suggesting that ECS may reduce c-Myc protein level via ubiquitination-proteasomal degradation. Bcl-2 family proteins, caspase, and poly(ADP-ribose) polymerase (PARP) were investigated to determine the consequence of down-regulating c-Myc. Protein levels of Bcl-2, Bcl-X(L), Bax, and Bad showed no change, and cleavage of caspase-3 and PARP were not induced. However, phosphorylation of Bad at Ser-155 and binding of Bad to 14-3-3 increased without binding to Bcl-X(L) after repeated ECS, implying that repeated ECS sequesters apoptotic Bad and frees pro-survival Bcl-XL. Taken together, c-Myc down-regulation via ubiquitination-proteasomal degradation and Bad inactivation by binding to 14-3-3 may be anti-apoptotic mechanisms elicited by repeated ECS in the rat frontal cortex. This finding further supports the trophic effect of ECS blocking apoptosis as a possible therapeutic effect of ECT.
Jeon
Won Je
WJ
Clinical Research Institute, Seoul National University Hospital, Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Seoul 110-744, Korea.
Kim
Se Hyun
SH
Seo
Myoung Suk
MS
Kim
Yeni
Y
Kang
Ung Gu
UG
Juhnn
Yong-Sung
YS
Kim
Yong Sik
YS
D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D004565:Electroconvulsive Therapy / Q000009:adverse effects*; D005625:Frontal Lobe / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010507:Periodicity; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D054875:Ubiquitination; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D048948:14-3-3 Proteins; C494821:Bad protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051025:bcl-Associated Death Protein
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