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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳小梨(Show-Li Chen) | |
| dc.contributor.author | Ping-Chang Kuo | en |
| dc.contributor.author | 郭秉昌 | zh_TW |
| dc.date.accessioned | 2021-06-17T00:38:12Z | - |
| dc.date.available | 2017-03-02 | |
| dc.date.copyright | 2012-03-02 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-01-31 | |
| dc.identifier.citation | Abate-Shen, C., and Shen, M.M. (2000). Molecular genetics of prostate cancer. Genes Dev 14, 2410-2434.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66481 | - |
| dc.description.abstract | BCAS2是一個小分子量的核蛋白質(26kDa)。在前人的研究中發現其為雌性素受體的一個轉錄共同活化因子。本研究中我們發現BCAS2可以直接與p53蛋白質結合。在一般狀況下BCAS2會輕微且持續性地減低p53蛋白質進而降緩了p53蛋白質的轉錄活性。然而當DNA發生損傷時, BCAS2則顯著的減低p53蛋白質，藉由這樣的作用方式來抵抗doxorubicin這類化療藥物對細胞所造成的傷害。在p53野生型的細胞中，抑制BCAS2的表現會誘發細胞自裁作用，但是在不俱有p53或是p53突變型的細胞中，抑制BCAS2則會使細胞生長週期停滯在G2/M時期。在抑制p53野生型細胞中BCAS2的表現時，至少有兩個導制細胞自裁的作用機制被啟動，其一為增加了細胞核中p53蛋白質的滯留，進而啟動了細胞自裁相關基因的表現；其二為增加p53蛋白質上Ser46氨基酸磷酸化程度，藉此提高了p53蛋白質的轉錄活性，以及減少p53蛋白質上Ser315氨基酸磷酸化程度，從而降低了p53被降解的作用。
此外，BCAS2也是一個與雄性素受體結合的蛋白質，在雄性素受體所調控的基因表現中，其俱有轉錄共同因子的功能。在臨床攝護腺癌樣本的分析中，我們發現於攝護腺癌樣本中BCAS2蛋白質的表現俱有顯著性的上升趨勢，並且與雄性素受體的表現情形呈現正相關性。而進一步對於BCAS2導致雄性素受體蛋白質增加的機制的研究時，我們發現BCAS2增強雄性素受體蛋白質半衰期的原因，一部分是由於BCAS2抑制了p53蛋白質的表現進而提高了AR的轉錄活性，此為一個p53相關的轉錄調控途徑。而在不俱有p53的細胞中，BCAS2也可以增加雄性素受體蛋白質，顯示了還有另一個與p53非相關的蛋白酶體調控途徑的存在。此外，降低BCAS2表現時，可以增加攝護腺癌細胞對於抗癌藥物17-AAG的敏感性，這顯示利用BCAS2的干擾RNA與已知的抗癌藥物進行合併治療時，將有可能達到更有效力的治療結果。 總結以上的結果，我們發現BCAS2俱有雙重的角色，其一為p53蛋白質的負調控因子，另一則是雄性素受體的保護因子。這些結果顯示BCAS2 將來可以作為攝護腺癌的一個臨床診斷標記，並且可作為一個發展癌症治療藥物的重要標靶。 | zh_TW |
| dc.description.abstract | BCAS2 is a small nuclear protein (26 kDa). It was reported previously as a transcriptional coactivator of estrogen receptor. Here, we report that BCAS2 directly interacts with p53 to reduce p53 transcriptional activity by mildly but consistently decreasing p53 protein in the normal condition. However, in the presence of DNA damage, BCAS2 prominently reduces p53 protein and provides protection against chemotherapeutic agent such as doxorubicin. Deprivation of BCAS2 induces apoptosis in p53 wild-type cells but causes G2/M arrest in p53-null or p53 mutant cells. There are at least two apoptosis mechanisms induced by silencing BCAS2 in wild-type p53-containing cells. Firstly, it increases p53 retention in nucleus that triggers the expression of apoptosis-related genes. Secondly, it increases p53 transcriptional activity by raising p53 phosphorylation at Ser46 and decreases p53 protein degradation by reducing p53 phosphorylation at Ser315.
Additionally, BCAS2 is AR interacting protein and functions as a transcription cofactor for AR-mediated gene expression. In clinical prostate cancer specimen analysis, we found that BCAS2 protein is significantly increased and positively correlates with AR level. To further study the mechanisms of BCAS2-increasing AR protein, we discovered that BCAS2 enhances AR protein half life partly from a p53-dependent transcriptional pathway, due to BCAS2 decreases p53 protein resulting in the raise of AR transcription activity. The other reason comes from p53-independent proteasomal pathway; due to BCAS2 can increase AR protein in p53 null cells. Furthermore the diminution of BCAS2 could enhance the sensitivity of prostate cancer cells to anticancer drug 17-AAG; suggesting RNAi targeting BCAS2 can be used in combination with known anti-cancer drugs for effective cancer treatment. In sum, we show that BCAS2 has a dual role one for a negative regulator of p53 and the other for a protector of AR. These results suggest that BCAS2 can be a diagnosis marker of prostate cancer that may be a critical target for developing therapeutic agents against cancer. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T00:38:12Z (GMT). No. of bitstreams: 1 ntu-101-D95445007-1.pdf: 4904474 bytes, checksum: 7a45601a8197cde0782d7f468b4987b9 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
誌謝 II 中文摘要 III ABSTRACT V CONTENTS 1 CHAPTER 1 5 INTRODUCTION 5 1.1 AIMS OF THIS STUDY 9 1.1.1 Aim I. BCAS2 functions for p53 protein regulation 9 1.1.2 Aim II. BCAS2 functions for AR protein regulation 11 CHAPTER 2 14 MATERIALS AND METHODS 14 2.1 ANTIBODIES 14 2.2 PLASMID CONSTRUCTION 15 2.3 CELL CULTURE 16 2.4 TRANSFECTION 17 2.4.1 Electroporation Method 17 2.4.2 Calcium Phosphate Method 18 2.5 GST PULL-DOWN ASSAY 19 2.6 IN VITRO BINDING ASSAY 20 2.7 CO-IMMUNOPRECIPITATION AND WESTERN BLOT ANALYSIS 21 2.8 TRANSIENT-TRANSFECTION AND LUCIFERASE ASSAY 22 2.9 NUCLEAR/CYTOPLASM FRACTION 23 2.10 RNA EXTRACTION AND REVERSE TRANSCRIPTION 24 2.11 REAL-TIME QUANTITATIVE PCR 25 2.12 CHROMATIN IMMUNOPRECIPITATION-QUANTITATIVE PCR ASSAY 27 2.13 IMMUNOFLUORESCENCE STAINING ASSAY 28 2.14 CELL CYCLE ANALYSIS 28 2.15 CELL PROLIFERATION ASSAY 29 2.16 IMMUNOHISTOCHEMISTRY STAINING ASSAY 30 2.17 DRUG SENSITIVITY ANALYSIS BY MTT ASSAY 30 2.18 RECOMBINANT LENTIVIRUS PRODUCTION AND INFECTION 31 2.19 STATISTICAL ANALYSIS 32 CHAPTER 3 33 RESULTS 33 3.1 PART I. BCAS2, A NOVEL REGULATOR OF THE P53 TUMOR SUPPRESSOR 33 3.1.1 Protein-protein interaction between BCAS2 and p53 tumor suppressor 33 3.1.2 Overexpression of BCAS2 reduces p53 protein and transcriptional activity 34 3.1.3 Reciprocal binding domains between BCAS2 and p53 36 3.1.4 Depletion of BCAS2 affects p53-dependent transcription 37 3.1.5 Reducing BCAS2 expression affects p53 protein stability, nuclear retention and post-translational modifications 39 3.1.6 Reducing the expression of BCAS2 increases p53-dependent apoptosis in cancer cells 42 3.1.7 Ectopic overexpression of BCAS2 rescues p53-mediated growth inhibition 44 3.2 PART II. BCAS2 INCREASE AR PROTEIN ACTIVITY VIA P53-DEPENDENT TRANSCRIPTION AND INHIBITION OF PROTEASOME DEGRADATION 46 3.2.1 BCAS2 and AR expression are significantly associated with prostate cancer 46 3.2.2 BCAS2 and AR physically interact in prostate cancer cells 47 3.2.3 BCAS2 enhances AR mRNA and protein activity in prostate cancer cells through a p53-dependent pathway 48 3.2.4 BCAS2 can also enhance AR protein activity in prostate cancer cells through a p53-independent pathway 50 3.2.5 BCAS2 rescues AR protein degradation by HSP90 inhibitor treatment 53 3.2.6 Knockdown BCAS2 can increase 17-AAG cancer drug sensitivity to inhibit prostate cancer cell proliferation 55 CHAPTER 4 56 DISCUSSION 56 4.1 PART I. BCAS2, A NOVEL REGULATOR OF THE P53 TUMOR SUPPRESSOR 56 4.2 PART II. BCAS2 INCREASE AR PROTEIN ACTIVITY VIA P53-DEPENDENT TRANSCRIPTION AND INHIBITION OF PROTEASOME DEGRADATION 60 CHAPTER 5 69 CONCLUSION 69 CHAPTER 6 71 FIGURES AND TABLES 71 6.1 FIGURES 72 Figure 1. Interaction between BCAS2 and p53 in vitro and in vivo. 72 Figure 2. BCAS2-p53 complexes repress p53-mediated p21 promoter activity. 73 Figure 3. Analysis of the mutual binding domains between BCAS2 and p53 proteins. 74 Figure 4. Depletion of BCAS2 expression increases the p53 transcriptional activity. 76 Figure 5. Effect of BCAS2 on p53 protein stability, nuclear retention, and post-translational modifications. 78 Figure 6. Biological significance of BCAS2 effects. 80 Figure 7. BCAS2 and AR were significantly overexpressed in prostate cancerous tissues. 82 Figure 8. BCAS2 associates with AR both in vitro and in vivo. 84 Figure 9. BCAS2 enhances AR mRNA, protein and transcriptional activity via p53-dependent in LNCaP cells. 86 Figure 10. BCAS2 increases AR protein in p53-independent pathway. 89 Figure 11. BCAS2 enhances AR protein stability. 90 Figure 12. Identify the BCAS2 interaction domains of AR. 92 Figure 13. BCAS2 rescues nuclear and cytosol AR protein degradation induced by geldanamycin in LNCaP cells. 93 Figure 14. BCAS2 RNAi can increase drug sensitivity of HSP90 inhibitor 17-AAG. 94 6.2 TABLES 95 Table 1. Identification of siRNA constructs against BCAS2. 95 Table 2. Cell cycle analysis of MCF-7 cells (wt p53) treated with shRNA construct of BCAS2 at 72 hr post-transfection. 96 Table 3. Cell cycle analysis of H1299 cells (null p53) treated with various shRNA constructs against BCAS2 at 96 hr post-transfection. 97 Table 4. Cell cycle analysis of C33A (mutant p53) cells treated with various shRNA constructs against BCAS2 at 96 hr post-transfection. 98 Table 5. Cell cycle analysis of MCF-7 cells treated with the various shRNA constructs of BCAS2 and p53, from three independent experiments described in Figure 6E. 99 Table 6. Cell cycle analysis of MCF-7 cells, rescued from doxorubicin-induced growth arrest by BCAS2 expression, from three independent experiments shown in Figure 6F. 100 CHAPTER 7 101 REFERENCES 101 CHAPTER 8 115 APPENDIX 115 | |
| dc.language.iso | en | |
| dc.title | BCAS2調控p53與雄性素受體蛋白質功能之研究 | zh_TW |
| dc.title | BCAS2 Regulates the p53 and Androgen Receptor Proteins' Functions | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 顧記華(Jih-Hwa Guh),葉秀慧(Shiou-Hwei Yeh),李明學(Ming-Shyue Lee),吳君泰(June-Tai Wu) | |
| dc.subject.keyword | BCAS2,p53,p21,雄性素受體,攝護腺癌,細胞自裁, | zh_TW |
| dc.subject.keyword | BCAS2,p53,p21,Androgen receptor,Prostate cancer,Apoptosis, | en |
| dc.relation.page | 131 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-01-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| Appears in Collections: | 微生物學科所 | |
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