期刊
TOXICOLOGY LETTERS
卷 224, 期 3, 页码 362-370出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2013.11.003
关键词
2,3,7,8-Tetrachlorodibenzo-p-dioxin; (TCDD); Microglia; Proliferation; Cyclin D1; Akt; Glycogen synthase kinase-3 beta (GSK-3 beta)
类别
资金
- National Natural Science Foundation of China [21077061, 21277078]
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that induces apoptosis of neurons and a pro-inflammatory response in microglial cells. First, we found that TCDD induced proliferation of HAPI microglial cells in a dose-and time-dependent manner. Flow cytometry analysis showed that this proliferation by TCDD was due to mainly enhancing the G1 to S phase transition. Next, it was found that TCDD treatment led to up-regulation of cyclin D1, which induces cell cycle progression from G1 to S phase, in a time-dependent manner. As for molecular mechanism, we revealed that TCDD was capable of inducing Akt phosphorylation and activation, resulting in phosphorylation and inactivation of glycogen synthase kinase-3 beta (GSK-3 beta). Inactivated GSK-3 beta attenuated proteasomal degradation of cyclin D1 by reducing Thr(286)-phosphorylated cyclin D1 levels. Moreover, inactivated GSK-3 beta increased cyclin D1 gene transcription by increasing its transcription factor beta-catenin in the nucleus. Further, blockage of phosphoinositide 3-kinase/Akt kinase with their specific inhibitors, LY294002 and Akt 1/2 kinase inhibitor, significantly reduced TCDD-enhanced proliferation of HAPI microglial cells. In conclusion, TCDD stimulates proliferation of HAPI microglial cells by affecting the Akt/GSK-3 beta/cyclin D1 signaling pathway. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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