期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 38, 期 5, 页码 809-822出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X17702668
关键词
Brain microvascular endothelial cells; GM-CSF; miR-96; ERG; c-MYC; ZO-1
资金
- National Natural Science Foundation of China [31171291, 31571057]
- Research Fund for the Doctoral Program of Higher Education of China [20132104110019]
- Ministry of Education Innovation team project [2012CB722405]
- Liaoning Provincial Department of Education Key Laboratory project [LZ2015074]
The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases in some disorders such as vascular dementia, Alzheimer's disease, and multiple sclerosis. We previously reported that in Alzheimer's disease patients, a high level of GM-CSF in the brain parenchyma downregulated expression of ZO-1, a blood-brain barrier tight junction protein, and facilitated the infiltration of peripheral monocytes across the blood-brain barrier. However, the molecular mechanism underlying regulation of ZO-1 expression by GM-CSF is unclear. Herein, we found that the erythroblast transformation-specific (ETS) transcription factor ERG cooperated with the proto-oncogene protein c-MYC in regulation of ZO-1 transcription in brain microvascular endothelial cells (BMECs). The ERG expression was suppressed by miR-96 which was increased by GM-CSF through the phosphoinositide-3 kinase (PI3K)/Akt pathway. Inhibition of miR-96 prevented ZO-1 down-regulation induced by GM-CSF both invitro and invivo. Our results revealed the mechanism of ZO-1 expression reduced by GM-CSF, and provided a potential target, miR-96, which could block ZO-1 down-regulation caused by GM-CSF in BMECs.
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