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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 周涵怡(Han-Yi Chou) | |
| dc.contributor.author | Ya-Pei Peng | en |
| dc.contributor.author | 彭雅珮 | zh_TW |
| dc.date.accessioned | 2021-06-13T02:22:56Z | - |
| dc.date.available | 2014-10-03 | |
| dc.date.copyright | 2011-10-03 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-20 | |
| dc.identifier.citation | REFERENCE
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30962 | - |
| dc.description.abstract | 癌症幹細胞被認為具有類似幹細胞特性，能夠自我更新，促進腫瘤的增生與分化並負責腫瘤轉移。另外，它還具有抗化學治療及放射治療的能力。輔助轉錄因子TIF1β是一個epigenetic的調控者，其重要功能為藉由與HP1蛋白或其他染色質調控因子的結合，影響染色質的重組，進而去調控基因的表現。另外，TIF1β本身也被認為能夠被後轉譯修飾，包含磷酸化及sumo化。TIF1β的Serine473位於其與HP1蛋白結合的序列附近，已被證實能夠藉由磷酸化來調控與HP1蛋白的結合。而TIF1β高度參與在維持胚胎幹細胞多能性的蛋白交互網絡之中，並能夠調控胚胎幹細胞多能性的維持與分化的過程。本文的研究利用肺癌幹細胞探討，發現了當細胞在失去了幹性之後，在S473磷酸化的TIF1β有明顯的受到調控，顯示出TIF1β-S473的磷酸化會參與癌症幹細胞的幹性維持。藉由免疫組織染色我們也發現TIF1β-S473的磷酸化確實與癌細胞侵犯及抗藥性相關。此外，在使細胞暴露於缺氧的系統之下，TIF1β-磷酸化的狀態和HIF1α的誘導有相反的情況，並且會影響到HIF1α的轉錄活性，而且在具有抗化療的病人組織中，TIF1β和HIF1α有高度相似的表現。這些證據暗示了TIF1β-S473的磷酸化可能在癌症幹細胞的幹性維持上扮演了重要角色，且可能經由與HIF1α交互調控，進而導致腫瘤的復發，轉移及抗性的發展。 | zh_TW |
| dc.description.abstract | Cancer stem cells were initially defined by their extensive self-renewal capacity, tumorigenicity, multipotentiality, and drug resistance. Transcription intermediary factor 1 beta (TIF1β) is an epigenetic modulator that can regulate chromatin remodeling and gene expression through the interaction with heterochromatin protein 1 (HP1) among other chromatin factors. The serine 473 residue of TIF1β is located just upstream of the HP1 binding domain of TIF1β, and has been shown to alter its association with HP1. Furthermore, TIF1β was previously identified as a component of the central protein interaction networks for maintenance of pluripotency in mouse embryonic stem cells. TIF1β is highly expressed in cancer; however, the role of TIF1β in tumorigenesis and its contribution to the maintenance of stemness properties in cancer stem cells have never been addressed. Using lung cancer stem cell models, we report that phosphorylation of TIF1β at the S473 residue is suppressed upon loss of stemness properties, and this phosphorylation state could occur in cancer progression events by immunohistochemistry analysis. Interestingly, we found that the phosphorylation status of TIF1β Ser473 inversely correlates with HIF1α induction during hypoxic stress. We also found that this phosphorylation state could influence the transcriptional activity of HIF1α, but we could not identify that HIF1α is associated with TIF1β-containing immunocomplexes. In addition, TIF1β is highly colocalized with HIF1α in chemo-resistant lung cancer patients. Taken together, our results suggest that phosphorylation of TIF1β at the S473 residue may play roles in regulating stemness in cancer stem cells, and may hence contribute to tumor recurrence, metastasis and the development of resistance to therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T02:22:56Z (GMT). No. of bitstreams: 1 ntu-100-R98450003-1.pdf: 31461941 bytes, checksum: a82fe234ab75c8c9763826c89dbc563f (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | CONTENTS
中文摘要 …………………………………………………………………...………...I ABSTRACT …………………………………………..…………….…....…..……...II CONTENTS ………………………………………………………….…….…..…….1 INTRODUCTION …………………………………………………………...……....7 -- Concept of cancer stem cells ……………….............................................................7 -- Hypothesis and Approach ………………………...……………...…………..…......8 -- Hypoxia and cancer stem cells .……………………………..….…………………..9 -- Transcription intermediary factor 1 beta (TIF1β) ……………………....…....……11 MATERIALS AND METHODS ……………………………..…..………..….…...14 -- DNA constructs and antibodies ………………………..………………….....…....14 -- Cell culture and transfection …………………………..……..………..…...…...…14 -- Hypoxia experiments …………………………………………………...…………15 -- Side population and Immunoflurorescence staining ………………………………16 -- Immunopreipitation ………………...……………………………...……………...17 -- Western blot analysis …...........................................................................................17 -- Immunohistochemistry …………………………………………………….….…..18 -- Luciferase assay ………………………………………………………….………..18 RESULTS ……………………………………………………………….………......20 -- Context sequence around TIF1β-S473 is conserved among mammals …………...20 -- Phosphorylation of TIF1β at S473 may be involved in regulating stemness of cancer stem cells …………………………………………………………………..20 -- Fluctuation of TIF1β-S473 phosphorylation during cancer progression ………….23 -- TIF1β-pS473 inversely correlates with HIF1α induction upon hypoxic induction..23 -- TIF1β-pS473 could affect on the transcriptional activity of HIF1 proteins ...…….26 -- The enhancement of HIF1α transcriptional activity is independent from the sumoylation status of TIF1β …………………………………...………..28 -- TIF1β-pS473 is highly expressed in stage IIIA of non-small cell lung cancer with chemo-resistance …………………….……………………………………………29 DISCUSSION …………………………………………………….……...…………31 FUTURE WORK …………………………………………………………………..36 -- Part 1: The functional studies of TIF1β-pS473 on HIF1α transactivation ………..36 -- Part 2: The correlation between TIF1β-pS473 and cancer stem cells in vivo ….….36 -- Part 3: SUMOylation research of TIF1β and HIF1α ……………………….……..37 -- Part 4: The studies of HIF2α involving in TIF1β-pS473 ………………………….37 REFERENCES ……………………………………………………..……...…….....39 FIGURES LEGENDS ……………………………………………….…...….……..52 -- Sequence context around S473 is highly conserved among mammals ………...…52 -- Phosphorylation of TIF1β at S473 is suppressed in lung cancer stem-like cells ....53 -- Isolation of lung cancer stem-like cells by side population cells sorting from A549 cells …………………………………………………………………….…..54 -- Phosphorylation of TIF1β at S473 is suppressed in cancer stem-like side population A549 cells ……………………………………………….……….55 -- Phosphorylation of TIF1β at S473 is suppressed in cancer stem-like side population A549 cells ……………………………………………….……….56 -- Phosphorylation of TIF1β at S473 is suppressed under long-term hypoxic Conditions ………………………………………………………………………...57 -- Long-term hypoxic conditions suppres phosphorylation of TIF1β at S473 in the interphase cell population …………………………………………………………58 -- Phosphorylation of TIF1β at S473 is suppressed during cancer progression ……..59 -- Phosphorylation of TIF1β at S473 inversely correlates with HIF1α induction upon hypoxic induction …………………………………………………………………60 -- TIF1β phosphorylation at S473 inversely correlates with HIF1α induction upon hypoxic-mimicking induction ………………………………………………...…..61 -- Fluctuation of TIF1β phosphorylation at S473 upon hypoxic treatment ………….62 -- TIF1β phosphorylation at S473 inversely correlates with HIF1α induction upon hypoxic-mimicking induction in HEK293T cells ………………………………...63 -- S473 non-phosphorylatable form of TIF1β promotes transactivation of HIF1α ….64 -- TIF1β transactivation on HIF1α transcriptional activity in the presence of ectopically expressed HIF1α ………………………………………………..…….65 -- Effect of TIF1β transactivation on ectopically expressed HIF1α ODD mutants ….66 -- Immunocomplex analysis for HIF1α components associated with TIF1β ……..…67 -- HIF2α is presented in TIF1β-containing immunocomplexes ..................................68 -- Sumoylation of TIF1β is independent of hypoxic mimicking stimulation ……..…69 -- HIF1α may contribute to the de-sumoylation of TIF1β ………………….………..70 -- Expression of HIF1α in chemoresistant lung cancer is highly correlated with TIF1β-pS473 …………………………………………………………………...…71 SUPPLEMENTARY DATA ………………………………………………....…….72 -- Isolation and establishment of lung cancer stem-like cell lines CLS1 and CLS1-2 …………………………………………………………………………....72 -- Experimental scheme of the procedures for hypoxic induction ……………….….73 -- Schematic representation of the plasmid expression vectors harboring Flag-TIF1β-WT, Flag-TIF1β-S473A , and Flag-TIF1β-S473E constructs ……….74 -- Schematic representation of the phosphorylation of TIF1β at S473 status and transactivation effect of HIF1α in cancer or cancer stem cells …………..……….75 APPENDIX ………………………………………………………………..…….….76 -- The hypothesis of cancer stem cells ……………………………………...……….76 -- Acquired capabilities of cancer stem cells …………………………………..……76 -- Mutations in stem cells and/or progenitor cells might give rise to cancer stem cells ………………………………………………………….………77 -- Factors and signaling pathways involved in the regulation of self-renewal of stem cells ………………………………………………………………………77 -- A protein interaction network for pluripotency of embryonic stem cells ………...78 -- The expression of TIF1β in various cancer tissues which were published from Human Protein Atlas website ……………………………………………………..79 -- Hypoxia and the hypoxia inducible factors (HIFs) can promote the stem-like phenotype …………………………………………..……………………………..80 -- Characterization of monoclonal anti-TIF1β and rabbit polyclonal anti-phosphorylated TIF1β on S473 antibodies …………………………………..80 -- Proposed mechanism that represses the HIF-1a transactivation by pVHL, VHLaK protein and TIF1β/KAP1 ………………………………..……………….81 -- Schematic of the HIF1α domain structure, function of individual domains, and the sites of post-translational modifications …………………………………………..81 -- Oxygen sensors contribute to the destruction and inactivation of HIF-1α by addition of hydroxyl group on Pro402, Pro564, and Asn803 ………….………….82 -- The HIF1 pathway in normoxia and hypoxia ……………………………………..82 -- Genes that are transcriptionally activated by HIF-1 …………………………...….83 -- The mechanism of SUMOylation …………………………………….…………...84 -- Coordinating posttranslational modifications of HIF1α ……………….………….84 -- Efficiently knockdown TIF1β by four different siRNAs and result in increasing the percentage of differentiation cells …………………………………………….85 | |
| dc.language.iso | en | |
| dc.subject | 癌症幹細胞 | zh_TW |
| dc.subject | HIF1α | zh_TW |
| dc.subject | 幹性維持 | zh_TW |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | TIF1β | zh_TW |
| dc.subject | cancer stem cells | en |
| dc.subject | TIF1β | en |
| dc.subject | stemness | en |
| dc.subject | hypoxia | en |
| dc.subject | HIF1α | en |
| dc.title | 探討TIF1β於癌幹細胞之幹性維持上所扮演的角色 | zh_TW |
| dc.title | Participation of TIF1β in Regulating Stemness of Cancer Stem Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳敏慧(Min-Huey Chen),沈湯龍(Tang-Long Shen) | |
| dc.subject.keyword | 癌症幹細胞,TIF1β,幹性維持,缺氧,HIF1α, | zh_TW |
| dc.subject.keyword | cancer stem cells,TIF1β,stemness,hypoxia,HIF1α, | en |
| dc.relation.page | 85 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-08-21 | |
| dc.contributor.author-college | 牙醫專業學院 | zh_TW |
| dc.contributor.author-dept | 口腔生物科學研究所 | zh_TW |
| 顯示於系所單位： | 口腔生物科學研究所 | |
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