Global gene profiling of (-)-Epigallocatechin-3-gallate (EGCG)-induced neuronal death
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Minghui Jessica Chen
PROVIDER: E-GEOD-22996 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The inhibition of DYRK1A (Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A) activity, triplicated in trisomy 21 subjects, has been proved as a promising therapy for Down syndrome. Epigallocatechin-3-gallate (EGCG), a polyphenol of green tea, is an allosteric inhibitor of DYRK1A that showed beneficial pro-cognitive effects in clinical trials with DS individuals. However, EGCG induces several pharmacological effects, and there is no proof that the observed improvements result from DYRK1A inhibition. Besides, the direct consequences of Dyrk1A overexpression are not well defined. We therefore used quantitative proteomics to decipher the proteome and phosphoproteome alterations resulting from Dyrk1A overexpression and its inhibition to get insight into the mechanism of action of EGCG. Towards this aim, we used mice overexpressing Dyrk1A, and compared the hippocampal proteome and phosphoproteome with their wild type counterparts, in basal conditions, and after treatment with EGCG. Moreover, given that the human clinical trials found that the effects of EGCG potentiated the effects of cognitive stimulation, we also included in our study treatment with environmental enrichment and its combination with EGCG. We found that DYRK1A overexpression leads to alterations in protein and phosphoprotein levels of hundreds of proteins, and that the levels of proteins involved in key postsynaptic pathways are restored by the cognitive enhancer treatments, which could help conceiving new therapeutic strategies.
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Project description:Epigallocatechin gallate (EGCG), the major green tea polyphenol, has been a subject of global interest as a potential chemopreventive or chemotherapeutic supplement for breast cancer. While on one hand epidemiological studies suggest inverse correlation between green tea consumption and breast cancer risk, investigations using cell culture and animal models of breast carcinogenesis on the other hand have demonstrated antiproliferative, antitumor, anti-invasive and anti-metastatic properties of EGCG. Mechanism of how EGCG affects cell proliferation, apoptosis, migration and cell cycle by affecting the function of a wide range of molecular targets have also been studied. However, the question as to how EGCG impacts on estrogen responsive genes has not been addressed. This issue is of relevance to our notion of EGCG as a potential chemopreventive or chemotherapeutic agent against breast cancer, which is estrogen dependent in majority of the newly diagnosed cases. Here, using the estrogen receptor α (ERα) positive MCF-7 breast cancer cells as a model, we have examined the effect of EGCG on the estrogen regulated genes.
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Project description:Epigallocatechin-3-gallate (EGCG), a major active polyphenol of green tea, has been shown to downregulate inflammatory responses in macrophages; however, the underlying mechanism has not been understood. Recently, we identified the 67-kDa laminin receptor (67LR) as a cell-surface EGCG receptor that mediates the anti-cancer action of EGCG at physiologically relevant concentrations (0.1-1 mM). Here we show the molecular basis for the downregulation of TLR4 signal transduction by EGCG at 1 mM in macrophages. Anti-67LR antibody treatment or RNAi-mediated silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on LPS-induced activation of downstream signaling pathways and target gene expressions. Additionally, we found that EGCG reduced the TLR4 expression through 67LR. Interestingly, EGCG induced a rapid upregulation of Tollip protein, a negative regulator of TLR-signaling, and this EGCG action was prevented by 67LR silencing or anti-67LR antibody treatment. RNAi-mediated silencing of Tollip impaired the TLR4 signaling inhibitory activity of EGCG. Taken together, these findings demonstrate that 67LR plays a critical role in mediating anti-inflammatory action of a physiologically relevant EGCG and Tollip expression could be modulated through 67LR. These results provide a new insight into the understanding of negative regulatory mechanisms for TLR4 signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.
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