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- 저자 : ( Noelia Che ) (검색결과 1 건)
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( Noelia Che ),( Kai Yu Ng ),( Man Tong ),( Michael Sy Huen ),( Xin Yuan Guan ),( Stephanie Ma ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1
Aims: Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis including degradation of damaged organelles and unwanted proteins as well as the support of cellular biosynthesis in response to environmental stress, preventing cells from undergoing apoptosis. We investi gated the functional role of protein arginine methyltransferase 6 (PRMT6) in regulation of autophagy and sorafenib resistance, aiming to provide novel therapeutic insights for HCC. Methods: We characterised the regulatory role of PRMT6 in autophagy by immunofluorescence puncta staining, transmission electron microscopy and immunoblot analyses. Identification and validation of potential PRMT6-interacting partners were per formed through tandem affinity purification coupled with mass spectrometry profiling followed by co-immunoprecipitation. Sub sequent in vitro and in vivo methylation assays found PRMT6 to methylate its binding partners to mediate arginine methylation for post-translational modification of proteins. Lentiviral-based overexpression and knockdown approaches were utilised to examine and explore the functional role of PRMT6-downstream effector in PRMT6-mediated autophagy deregulations in HCC. Results: Upon autophagy induction by Earle’s Balanced Salt Solution (EBSS) to mimic nutrient deprivation, hypoxia to mimic oxygen deprivation and sorafenib treatment, we demonstrated a negative correlation between expression of PRMT6 and LC 3BII in HCC. Intriguingly, we identified and validated a number of autophagy-related proteins from mass spectrometry-based proteomics, including Bcl-2 associated athanogene 5 (BAG5), as PRMT6-binding partners. Mechanistically, PRMT6 methylates BAG5, leading to its protein degradation. We later confirmed that, BAG5, a downstream effector of PRMT6, promotes HCC tumorigenesis through autophagic alterations in vitro and in vivo. More importantly, data-mining in The Cancer Genome Atlas (TCGA) - Liver Cancer dataset found patients with higher BAG5 expression to display a significantly worst survival out come, indicating its potential translational values. Conclusions: Our findings suggest PRMT6 down-regulation in HCC tumors to promote tumorigenicity and sorafenib resistance through an altered autophagic flux via BAG5 de-regulation.
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