Signal transduction of thapsigargin-induced apoptosis in osteoblast.
The toxicity of thapsigargin, a selective inhibitor of endoplasmic reticular Ca2+-ATPase, was investigated in osteoblasts. We induced apoptosis in murine osteoblastic MC3T3E1 cells by exposure to the thapsigargin. Thapsigargin transiently increased the phosphotransferase activity of c-Jun N-terminal kinases1 (JNK1), which might in turn activate transcriptional activity of activation protein-1 (AP-1). We then prepared extracts from thapsigargin-treated MC3T3E1 cells and monitored cleavage of acetyl-YVAD-AMC and acetyl-DEVD-AMC, fluorogenic substrates for caspase 1-like and caspase 3-like proteases, respectively. Thapsigargin significantly increased the proteolytic activity of caspase 3-like proteases, but not the activity of caspase 1-like proteases. Furthermore, thapsigargin increased the transcriptional activity of nuclear factor-kappaB (NF-kappaB). These data suggest that thapsigargin-induced apoptosis in osteoblasts may be via activation of JNK1, caspase 3-like family proteases, and transcriptional factors including AP-1 and NF-kappaB.
Chae
H J
HJ
Department of Dental Pharmacology and Institute of Wonkwang Biomaterial Implant, School of Dentistry, Wonkwang University, Chonbuk, South Korea.
Chae
S W
SW
Weon
K H
KH
Kang
J S
JS
Kim
H R
HR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D010006:Osteoblasts / Q000473:pathology* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D019284:Thapsigargin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019284:Thapsigargin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000252:Calcium-Transporting ATPases