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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華 | |
| dc.contributor.author | Fei-I Lien | en |
| dc.contributor.author | 連妃儀 | zh_TW |
| dc.date.accessioned | 2021-06-16T23:28:21Z | - |
| dc.date.available | 2017-07-31 | |
| dc.date.copyright | 2012-08-28 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-07-31 | |
| dc.identifier.citation | Adhikary, S., and Eilers, M. (2005). Transcriptional regulation and transformation by Myc proteins. Nature reviews Molecular cell biology 6, 635-645.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65172 | - |
| dc.description.abstract | The promyelocytic leukemia protein (PML) was identified in acute promyelocytic leukemia, in which chromosome translocation generates oncogenic PML-RARα fusion protein. The PML protein is essential for the assembly of PML-nuclear bodies (PML-NBs) and is a tumor suppressor. Through lentivirus-based shRNAs screening, previous study in our laboratory identified nine oncogenes and one tumor suppressor as putative regulators of PML-NBs. Using RNA interference and overexpression strategies to validate their effects on PML expression, we confirmed that Myc, Max, and Src are negative regulators of PML. We next investigated the mechanism underlying Myc/Max-induced PML downregulation. We observed that Myc/Max suppress PML mRNA expression and repress PML promoter activity. We further identified that a 0.2 kb PML promoter segment is responsible for Myc/Max binding and Myc/Max-mediated transcription repression. Besides transcriptional repression, we found that Myc/Max also accelerate PML protein turnover by increasing PML ubiquitiantion. Interestingly, this effect is not due to upregulation of previously identified PML E3 ligases RNF4 and KLHL20, but is likely mediated by a Cullin 4A/B-family of E3 ligase. In conclusion, our study identifies Myc/Max as PML negative regulators and indicates that Myc/Max regulate PML through both transcriptional and post-translational mechanisms. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T23:28:21Z (GMT). No. of bitstreams: 1 ntu-101-R99b46012-1.pdf: 1288953 bytes, checksum: dc070307828a1d1edc3390c8ee78bb50 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 摘要………………………………………………………………………………….i
Abstract…..……………………………………………………………………..….ii Introduction………………………………………………………………………..4 1 Tumorigenesis…………………………………………………………….......4 1.1 Tumor suppressor …………………………………………………..........…5 1.2 Oncoprotein…………………………………………………………………6 2 PML…………………………………………………………………………...7 2.1 PML function…………………………………………………………….....8 2.2 Transcriptional control of PML expression………………………………...9 2.3 Control of PML protein stability………………………………………......10 3 Myc…………………………………………………………………..……....11 3.1 Myc-mediated transcriptional regulation…………………...………….......12 3.2 The functional mechanisms of Myc in cell cycle progression……………..14 Preface……………………………………………………………………………..15 Materials and Methods……………………………………………………...…….16 Plasmid……………………………………………………………………….…16 Antibodies and reagents…………………………………………………...…....16 Cell culture and transient transfection……………………………………….…16 Western blot………………………………………………………………….....17 Establishment of tumor suppressor and oncogene knockdown cell lines by lentivirus system………………………………………………………………………......18 RT/real-timePCR………………………………………………………….……19 Luciferase assay………………………………………………………………...19 ChIP-qPCR assay……………………………………………………………..…19 Cycloheximide chase assay……………………………………………….……..20 In vivo ubiquitination assay……………………………………………..…….…21 Transcription factor binding sites prediction tool……………………………......21 Results……………………………………………………………………………….22 Validation of the putative PML regulators identified from shRNA screening by knockdown approach. ……………………………………………...………...….22 Validation of the putative PML regulators identified from shRNA screening by overexpression approach. …………………………………………..……………23 Myc/Max overexpression downregulate PML mRNA expression …………...…24 Mapping PML promoter region involved in Myc/Max-mediated PML downregulation.…………………………………….………………………….…24 Myc/Max are recruited to the 0.2 kb region of PML promoter…..………………25 The canonical E box and YY1 binding sites are not involved in Myc/Max-induced PML repression. …………………………………………………………...…….25 Myc/Max increased PML protein turnover through promoting PML-I ubiquitination in vivo. …………………………………………………………………………..26 Myc/Max cannot upregulate RNF4 and KLHL20, two known PML E3 ligases..27 Myc/Max promote PML-I ubiquitination through Cullin 4 in vivo..…………....27 Discussion…………………………………………………………………………...29 Table…………………………………………………………………………….…..33 Figures……………………………………………………………………………....34 Figure 1. Depletion of LATS1 fails to decrease PML protein level..…………...34 Figure 2. Increase of PML expression induced by shRNAs targeting SIK2, Myb, Fos, Fes, E2F1, and PIM1.……………………………………………..………..35 Figure 3. Increase of PML expression induced by shRNAs targeting Src, Myc, and Max..…………………………………………………………………………….36 Figure 4. Overexpression of SIK2, Myb, Fos, Fes, E2F1, or PIM1 fails to alter PML expression..………………………………………………………………………37 Figure 5. Overexpression experiments demonstrate the ability of Myc/Max and Src to downregulate PML protein..…………………………………………….....…38 Figure 6. Myc/Max overexpression downregulates PML mRNA expression…..39 Figure 7. Mapping PML promoter regions involved in Myc/Max-mediated PML downregulation..…………………………………………………..………….....40 Figure 8. Myc/Max are recruited to the 0.2 kb region of PML promoter..……..41 Figure 9. The canonical E box and YY1 binding sites are not involved in Myc/Max- induced PML repression..………………………………………………………42 Figure 10. Myc/Max increase PML protein turnover……..…………………....43 Figure 11. Myc/Max promote PML-I ubiquitination in vivo……….………......44 Figure 12. Myc/Max cannot upregulate RNF4 and KLHL20, two known PML E3 ligases………………………………………………………..……………...…..45 Figure 13. Myc/Max promote PML-I ubiquitination through Cullin 4 in vivo...46 Reference……………………………………………………………………….….47 | |
| dc.language.iso | en | |
| dc.subject | PML | zh_TW |
| dc.subject | Myc/Max | zh_TW |
| dc.subject | 轉錄調控 | zh_TW |
| dc.subject | 轉譯後蛋白質修飾 | zh_TW |
| dc.subject | PML | en |
| dc.subject | Myc/Max | en |
| dc.subject | transcription | en |
| dc.subject | post-translational modification | en |
| dc.title | 探討Myc/Max調控PML之機制 | zh_TW |
| dc.title | The Role of Myc/Max in PML Regulation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張久瑗,顏雪琪 | |
| dc.subject.keyword | PML,Myc/Max,轉錄調控,轉譯後蛋白質修飾, | zh_TW |
| dc.subject.keyword | PML,Myc/Max,transcription,post-translational modification, | en |
| dc.relation.page | 55 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-07-31 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-101-1.pdf 未授權公開取用 | 1.26 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。