AP-1-independent sensitization to oxidative stress-induced apoptosis by proteasome inhibitors.
Hydrogen peroxide (H(2)O(2)) induces apoptosis of mesangial cells via c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) and extracellular signal-regulated kinase (ERK)-AP-1 pathways. We recently found that subtoxic doses of proteasome inhibitors, MG132 and lactacystin, dramatically enhanced H(2)O(2)-induced apoptosis in mesangial cells. In this report, we examined molecular mechanisms involved in this phenomenon, especially focusing on AP-1 pathways. Reporter assays showed that MG132 induced activation of AP-1. However, pharmacological inhibitors of AP-1, retinoic acid, and curcumin, did not suppress the proapoptotic effect of MG132. Suppression of JNK-AP-1 by transfection with either a dominant-negative mutant of JNK or a dominant-negative mutant of c-Jun did not attenuate the apoptosis enhancement by MG132. Similarly, suppression of ERK-AP-1 by PD98059 or dominant-negative mutants of ERK did not affect the apoptosis-promoting effect of MG132. Interestingly, pretreatment with MG132 did not enhance activation of AP-1 by H(2)O(2). These data suggested a novel, AP-1-independent promotion of apoptosis by proteasome inhibitors.
Hiramatsu
Nobuhiko
N
Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho, Yamanashi 409-3898, Japan.
Kasai
Ayumi
A
Yao
Jian
J
Meng
Yiman
Y
Takeda
Masayuki
M
Maeda
Shuichiro
S
Kitamura
Masanori
M
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000502:physiology*
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D018808:Transcription Factor AP-1; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde