Abstract:
:Thymosin beta 4 (Tβ4), a secreted 43 amino acid peptide, promotes oligodendrogenesis, and improves neurological outcome in rat models of neurologic injury. We demonstrated that exogenous Tβ4 treatment up-regulated the expression of the miR-200a in vitro in rat brain progenitor cells and in vivo in the peri-infarct area of rats subjected to middle cerebral artery occlusion (MCAO). The up-regulation of miR-200a down-regulated the expression of the following targets in vitro and in vivo models: (i) growth factor receptor-bound protein 2 (Grb2), an adaptor protein involved in epidermal growth factor receptor (EGFR)/Grb2/Ras/MEK/ERK1/c-Jun signaling pathway, which negatively regulates the expression of myelin basic protein (MBP), a marker of mature oligodendrocyte; (ii) ERRFI-1/Mig-6, an endogenous potent kinase inhibitor of EGFR, which resulted in activation/phosphorylation of EGFR; (iii) friend of GATA 2, and phosphatase and tensin homolog deleted in chromosome 10 (PTEN), which are potent inhibitors of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, and resulted in marked activation of AKT; and (iv) transcription factor, p53, which induces pro-apoptotic genes, and possibly reduced apoptosis of the progenitor cells subjected to oxygen glucose deprivation (OGD). Anti-miR-200a transfection reversed all the effects of Tβ4 treatment in vitro. Thus, Tβ4 up-regulated MBP synthesis, and inhibited OGD-induced apoptosis in a novel miR-200a dependent EGFR signaling pathway. Our findings of miR-200a-mediated protection of progenitor cells may provide a new therapeutic importance for the treatment of neurologic injury. Tβ4-induced micro-RNA-200a (miR-200a) regulates EGFR signaling pathways for MBP synthesis and apoptosis: up-regulation of miR-200a after Tβ4 treatment, increases MBP synthesis after targeting Grb2 and thereby inactivating c-Jun from inhibition of MBP synthesis; and also inhibits OGD-mediated apoptosis after targeting EGFR inhibitor (Mig-6), PI3K inhibitors (FOG2 and Pten) and an inducer (p53) of pro-apoptotic genes, for AKT activation and down-regulation of p53. These findings may contribute the therapeutic benefits for stroke and other neuronal diseases associated with demyelination disorders.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Santra M,Chopp M,Santra S,Nallani A,Vyas S,Zhang ZG,Morris DCdoi
10.1111/jnc.13394subject
Has Abstractpub_date
2016-01-01 00:00:00pages
118-32issue
1eissn
0022-3042issn
1471-4159journal_volume
136pub_type
杂志文章abstract::A glutamate binding protein was purified from bovine brain to apparent homogeneity. The procedure used for the purification of this protein involved extraction of a crude synaptic membrane fraction with Na-cholate, followed by solubilization of the binding protein from the membranes by Triton X-100, and, finally, affi...
journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1985.tb12897.x
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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journal_title:Journal of neurochemistry
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pub_type: 杂志文章,评审
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2006.03819.x
更新日期:2006-06-01 00:00:00
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journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2000.740501.x
更新日期:2000-02-01 00:00:00
abstract::Fragile X syndrome (FXS) is a developmental disorder caused by the loss of Fragile X Mental Retardation 1 (FMR1) gene function because of a CGG repeat expansion (> 200 repeats) in the gene. The molecular mechanism(s) linking loss of FMR1 function to the molecular pathology and cognitive/behavioral disability remain un...
journal_title:Journal of neurochemistry
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