Multimolecular complex of Par-4 and E2F1 binding to Smac promoter contributes to glutamate-induced apoptosis in human- bone mesenchymal stem cells.
Neural cells undergo glutamate-induced apoptosis in ischaemic brain tissue, in which prostate apoptosis response-4 gene (Par-4) is involved. Human-bone mesenchymal stem cells can be utilized as an effective therapy for ischemic brain injury. In this study, we found that glutamate could induce apoptosis in human-bone mesenchymal stem cells, accompanied by increased expression of Par-4 gene and Smac release from mitochondria. Repressing Par-4 expression attenuated the glutamate-induced apoptosis. Both Par-4 protein and E2F1 protein could bind to E2F1-binding BS3 site on Smac promoter and participated in the formation of a proteins-DNA complex. Moreover, in the complex, E2F1, not Par-4, was found to be directly bound to the Smac promoter, suggesting that Par-4 exerted indirectly its transcriptional control on the Smac gene though interacting with E2F1. Expression of full-length Par-4 in human-bone mesenchymal cells resulted in increased activity of the Smac promoter. In addition, the indirect transcripional regulation of Par-4 on Smac depended on its COOH terminus-mediated interaction between Par-4 and E2F1. We conclude that the formation of proteins-DNA complex, containing Par-4 protein, E2F1 protein and the Smac promoter, contributes to the pro-apoptotic effect on glutamate-treated human-bone mesenchymal stem cells.
Lu
Chao
C
Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China. luchao8009@163.com
Chen
Jie-Qing
JQ
Zhou
Guo-Ping
GP
Wu
Sheng-Hua
SH
Guan
Ya-Fei
YF
Yuan
Chuan-Shun
CS
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C101296:prostate apoptosis response-4 protein; D018698:Glutamic Acid