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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳瑞華(Ruey-Hwa Chen) | |
| dc.contributor.author | Chiu-Lin Luan | en |
| dc.contributor.author | 欒玖霖 | zh_TW |
| dc.date.accessioned | 2023-03-20T00:16:34Z | - |
| dc.date.copyright | 2022-07-27 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-07-27 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/86769 | - |
| dc.description.abstract | 長鏈非編碼 RNA(LncRNA) 能調節許多生物反應，最近研究發現 lncRNAs 在自噬調節中扮演重要作用。然而目前對 lncRNAs 調控自噬的機制尚不清楚。本研究中，我們發現一種新型 lncRNA BCRP3 在多種腫瘤中的表達異常低，並做為自噬的正調節因子。進一步我們確認 BCRP3 主要位於細胞質中並能提高 VPS34 活性來啟動自噬。當細胞處於蛋白毒性刺激下會促進 BCRP3 的基因表現，進而促進泛素化蛋白質聚集體的清除。當蛋白質毒性刺激下， BCRP3 缺乏不僅影響蛋白質動態平衡的調節，還導致 TGF-β/Smad2 訊號被啟動，最後造成生長抑制、細胞凋亡。總上所述，我們研究揭示了 BCRP3 通過增強 Vps34 複合物的活性進而促進自噬作用來維持蛋白質動態平衡和細胞存活。 | zh_TW |
| dc.description.abstract | Long noncoding RNAs (LncRNAs) have been implicated in regulating many biological processes. Recent studies have also shown that lncRNAs play important roles in autophagy regulation. However, the underlying mechanism of lncRNAs in autophagy has not been unveiled. In this study, we identified a novel lncRNA BCRP3 as a positive modulator of autophagy and with abnormally low expression in a variety of tumors. BCRP3 is mainly located in the cytoplasm and binds to the VPS34 complex, which in turn initiates autophagy under basal and starvation conditions. In response to proteasome inhibition or oxidative stress-induced proteotoxicity, BCRP3 is upregulated to promote autophagy, thus facilitating the clearance of ubiquitinated protein aggregates. BCRP3 deficiency under proteotoxic stress not only comprises the protein quality control, but also leads to growth inhibition, cell death, and apoptosis. These cell survival defects are mediated in part through the upregulation of the TGF-/Smad2 pathway. In conclusion, our study revealed the role of BCRP3 as a positive regulator of autophagy by binding to VPS34 complex and BCRP3 is important for the maintenance of protein homeostasis and cell survival. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-20T00:16:34Z (GMT). No. of bitstreams: 1 U0001-2607202210153400.pdf: 2292818 bytes, checksum: f693efea0ef4edc87a3747c2bd5ce34d (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | Content I. Introduction 1 Autophagy 1 1. Autophagy in cancer 1 2. Mechanism of autophagy 2 3. The roles of autophagy in aggrephagy 5 Long non-coding RNAs (lncRNAs) 7 1. Functions of lncRNAs 7 2. lncRNA in cancer 8 3. lncRNA in autophagy 11 TGF-beta pathway 13 1. Mechanism of TGF-ꞵ pathway 13 2. The functions and mechanisms of TGF-ꞵ pathway in regulating cell cycle and cell survival 14 II. Materials and Methods 16 Oligonucleotides 16 Plasmids 16 Antibodies 16 Primers 17 Chemicals 17 Cell culture and transfection 17 Lentiviral package and transduction 18 Western blotting 18 Immunoprecipitation 19 Quantitative real-time PCR (qRT-PCR) 19 Subcellular fractionation assay 20 PI3K activity assay 20 BrdU incorporation and MTT assays 21 Bioinformatics 21 Statistics 22 III. Results 23 BCRP3 promotes autophagy 23 BCRP3 promotes autophagy by enhancing VPS34 activity 24 BCRP3 is upregulated under proteotoxic stresses to promote the accumulation of ubiquitinated proteins 25 BCRP3 deficiency under proteotoxicity leads to the accumulation of growth/survival inhibitors and TGF-β pathway upregulation 26 BCRP3 protects against proteotoxicity causing growth arrest and apoptosis by downregulating TGF-β signaling 27 V. Discussion 29 BCRP3 promotes protein homeostasis by activating autophagy 29 BCRP3 upregulates Vps34 enzymatic activity 29 BCRP3 is induced under proteasome inhibitor and oxidative stressor 30 BCRP3 affects growth inhibition, apoptosis and TGF-β/Smad2 pathway under proteotoxicity 31 The importance of BCRP3 in cancer 32 VI. Figure 34 Figure 1. BCRP3 gene expression level in various cancers and normal tissues. 34 Figure 2. Overexpression of BCRP3 increases the resistance of tumor cells to chemotherapy but does not affect DNA damage repair. 35 Figure 3. Autophagy inhibition reverses BCRP3-induced chemoresistance. 36 Figure 4. BCRP3 increases LC3 lipidation. 37 Figure 5. BCRP3 is mainly localized in cytoplasm. 38 Figure 6. BCRP3 enhances Vps34 activity. 39 Figure 7. BCRP3 is upregulated by certain proteotoxic stresses. 40 Figure 8. BCRP3 deficiency increases the accumulations of ubiquitinated proteins under proteotoxic stresses. 41 Figure 9. BCRP3 deficiency under proteotoxic stress leads to the accumulation of proteins in growth arrest, apoptosis, and TGF- pathway. 42 Figure 10. BCRP3 deficiency under proteotoxicity enhances TGF- signaling towards growth inhibition and apoptosis. 43 Figure 11. BCRP3 deficiency under proteotoxicity decreases proliferation and cell viability. 44 Figure 12. BCRP3 deficiency under proteotoxicity enhances apoptosis. 45 Figure 13. TGF-β pathway enhances apoptosis in MG132-treated cells. 46 Figure 14. The model showing the mechanism for BCRP3 in protein homeostasis and cell survival by activating autophagy. 47 VII Appendix 48 Appendix 1. BCRP3 deficiency impairs omegasome formation. 48 Appendix 2. BCRP3 deficient did not affect ULK1, mTOR, and AMPK. 49 Reference 50 | |
| dc.language.iso | en | |
| dc.subject | TGF-beta信號 | zh_TW |
| dc.subject | LncRNA | zh_TW |
| dc.subject | 自噬 | zh_TW |
| dc.subject | VPS34複合物 | zh_TW |
| dc.subject | 細胞死亡 | zh_TW |
| dc.subject | 癌症 | zh_TW |
| dc.subject | LncRNA | zh_TW |
| dc.subject | 自噬 | zh_TW |
| dc.subject | VPS34複合物 | zh_TW |
| dc.subject | TGF-beta信號 | zh_TW |
| dc.subject | 細胞死亡 | zh_TW |
| dc.subject | 癌症 | zh_TW |
| dc.subject | TGF-beta signaling | en |
| dc.subject | LncRNA | en |
| dc.subject | TGF-beta signaling | en |
| dc.subject | VPS34 complex | en |
| dc.subject | cancer | en |
| dc.subject | cell death | en |
| dc.subject | LncRNA | en |
| dc.subject | VPS34 complex | en |
| dc.subject | autophagy | en |
| dc.subject | autophagy | en |
| dc.subject | cancer | en |
| dc.subject | cell death | en |
| dc.title | 一種新型長鏈非編碼 RNA BCRP3 通過激活自噬促進蛋白質穩態和細胞存活 | zh_TW |
| dc.title | A novel long noncoding RNA BCRP3 promotes protein homeostasis and cell survival by activating autophagy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳光超(Guang-Chao Chen),朱雪萍(Hsueh-Ping Chu) | |
| dc.subject.keyword | LncRNA,自噬,VPS34複合物,TGF-beta信號,細胞死亡,癌症, | zh_TW |
| dc.subject.keyword | autophagy,cancer,cell death,LncRNA,TGF-beta signaling,VPS34 complex, | en |
| dc.relation.page | 54 | |
| dc.identifier.doi | 10.6342/NTU202201725 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-07-27 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 基因體與系統生物學學位學程 | zh_TW |
| dc.date.embargo-lift | 2022-07-27 | - |
| Appears in Collections: | 基因體與系統生物學學位學程 | |
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| U0001-2607202210153400.pdf | 2.24 MB | Adobe PDF | View/Open |
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