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系統識別號 U0026-2108201711185600
論文名稱(中文) 以肺癌模式探討AKT促進ZNF322A致癌蛋白質的穩定性及轉錄活性
論文名稱(英文) AKT promotes protein stability and transcriptional activity of ZNF322A oncoprotein in lung cancer
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 105
學期 2
出版年 106
研究生(中文) 陳玉婷
研究生(英文) Yu-Ting Chen
學號 S26044094
學位類別 碩士
語文別 英文
論文頁數 90頁
口試委員 指導教授-王憶卿
口試委員-洪文俊
口試委員-沈延盛
口試委員-蔣輯武
中文關鍵字 肺癌  AKT  ZNF322A  磷酸化  轉錄因子 
英文關鍵字 Lung cancer  AKT  ZNF322A  phosphorylation  transcription factor 
學科別分類
中文摘要 研究背景: ZNF322A為致癌轉錄因子。本實驗室先前發現ZNF322A會與c-Jun形成異源二具體,正向調控alpha-adducin (ADD1) 和cyclin D1 (CCND1) 基因的之表現,進一步促進腫瘤的生長及轉移。然而,對於調控ZNF322A蛋白質功能的轉譯後修飾及訊息傳遞路徑機制尚未釐清。
研究目的:本篇研究欲探討轉譯後修飾如蛋白質磷酸化對於ZNF322A蛋白質穩定性及轉錄活性之調控機制,並進一步研究其上游激酶 (kinase) 及其訊息傳遞路徑。
研究結果: 本研究利用蛋白質體學及蛋白質磷酸化資料庫分析,發現到一些ZNF322A磷酸化位點,而這些位點透過質譜分析被預測出可能受到AKT所調控。進一步以試管內激酶反應 (In vitro kinase assay) 證實了ZNF322A確實為AKT的激酶受質。在細胞實驗中,透過西方墨點法 (Immunoblot) 及雙螢光酶啟動子試驗 (Dual luciferase promoter assay) 證實AKT磷酸化ZNF322A能促進ZNF322A的蛋白質穩定性及轉錄活性。進一步分析四個AKT磷酸化ZNF322A的位點,發現ZNF322A Thr262位點被AKT磷酸化會促使ZNF322A蛋白質穩定性增加進而促進其對ADD1基因的轉錄活性;而AKT調控ZNF322A Thr150、Ser224、Thr234位點的磷酸化雖不改變其蛋白質穩定性,卻也能促使ZNF322A結合到ADD1與CCND1啟動子的區域上,正向調控ADD1及CCND1轉錄活性及基因表現,進一步促進肺癌細胞的增生及爬行。此外 epidermal growth factor 的刺激能夠活化AKT進一步維持ZNF322A的蛋白質穩定性及轉錄活性。在動物實驗中發現AKT與ZNF322A同時過表達較ZNF322A單獨過表達更能誘導肺癌細胞肺部轉移。由以上研究結果顯示AKT藉由磷酸化ZNF322A,正向調節ZNF322A的轉錄活性與致癌轉移功能。
結論:本篇研究發現AKT磷酸化ZNF322A不僅能促進蛋白質的穩定性,也能活化下游基因之轉錄調控,進而導致肺癌的形成;這些結果將在肺癌病人檢體進一步來驗證。未來,我們預期透過標靶藥物的治療能夠抑制ZNF322A的轉錄調控或是阻斷AKT訊息路徑的傳遞,進而達到治療癌症的效果。


英文摘要 Background: ZNF322A is an oncogenic zinc-finger transcription factor. Our published result shows that ZNF322A positively regulates alpha-adducin (ADD1) and cyclin D1 gene transcription to promote tumorgenicity of lung cancer. However, the upstream regulatory mechanisms of ZNF322A protein function are still unknown. Previously, our cell-based mass spectrometry analysis identified several ZNF322A phosphorylation sites which may be targeted by AKT, suggesting that ZNF322A may be a protein substrate of AKT.
Purpose: This study aimed to investigate the role of AKT in regulation of ZNF322A protein function and to identify the upstream signaling pathway involved in AKT-mediated ZNF322A functions.
Results: Our data demonstrated that AKT could phosphorylate ZNF322A by in vitro kinase assay. In cell-based studies, AKT indeed interacted with ZNF322A in lung cancer cells. Moreover, we found that overexpression of AKT promoted ZNF322A protein stability and transcriptional activity whereas these effects were inhibited by knocking down of AKT or treating with AKT inhibitor. In addition, ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, ZNF322A Thr-150, Ser-224, and Thr-234 phosphorylation by AKT enhanced ADD1 and CCND1 promoter activity without affecting protein stability. ChIP-qPCR assay showed that ZNF322A phosphorylation defective mutants T150A-, S224A-, and T234A-ZNF322A attenuated binding affinity to ADD1 and CCND1 promoter compared with wild-type (WT)-ZNF322A. Furthermore, AKT-mediated Thr-150, Ser-224, and Thr-234 phosphorylation promoted lung cancer cell proliferation and motility. In addition, we found that AKT-promoted ZNF322A protein stability and transcriptional activity could be regulated by epidermal growth factor receptor signaling. Consistently, experimental tumor metastasis assay showed that overexpression of WT-ZNF322A significantly increased tumor metastasis in vivo which was further enhanced by co-overexpression of AKT in comparison with control group.
Conclusions: This study provided the novel mechanism of AKT signaling axis in promoting ZNF322A protein stability and transcriptional activity in lung cancer cell and xenograft models. Further clinical validation will be performed. We proposed that therapeutic strategies by targeting ZNF322A oncoprotein for transcription suppressing or by blocking AKT signaling may provide new treatment for lung cancer patients.
論文目次 Introduction 1
I. Lung cancer
(A). Epidemiology of lung cancer 1
(B). Therapeutic targeting on epidermal growth factor receptor (EGFR) in lung cancer 1
II. AKT
(A). Role of AKT in lung cancer 2
(B). Therapeutic targeting on AKT in cancer 3
(C). Role of AKT in regulation of protein stability 4
(D). Role of AKT in regulation of transcription factor activity 5
III. Zinc finger transcription factor
(A). Overview of zinc finger transcription factor 6
(B). Role of zinc finger transcription factor in cancer 7
(C). Regulatory mechanism of protein stability on zinc finger transcription factor 8
(D). Regulatory mechanism of transcriptional activity on zinc finger transcription factor 9
(E). Previous studies of zinc finger 322A (ZNF322A) 10
Study basis and specific aims 11
I. To investigate whether AKT could phosphorylate ZNF322A and regulate ZNF322A protein stability and transcriptional activity 11
II. To verify which phosphorylation sites were responsible for ZNF322A protein stability and transcriptional activity 12
III. To examine whether growth factor signaling pathways such as EGFR involved in AKT-mediated ZNF322A protein function 12
IV. To perform in vivo xenograft analyses of AKT and ZNF322A protein phosphorylation 12
Materials and methods 13
I. Cell lines and culture conditions 13
II. Plasmids, RNAi and transfection 13
III. Site-directed mutagenesis 13
IV. Cloning, expression and purification of the human
ZNF322A recombinant protein 14
V. Drug treatment 15
VI. RNA extraction and quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) assays 15
VII. Immunoblotting 15
VIII. Cycloheximide chase assay 16
IX. Immunoprecipitation (IP) 16
X. Chromatin immunoprecipitation-polymerase chain reaction (ChIP-qPCR) assay 17
XI. Dual luciferase promoter assay 17
XII. Cell proliferation assay 17
XIII. Transwell migration assay 18
XIV. Experimental metastasis assay in vivo 18
XV. In vitro kinase assay 19
XVI. In-gel digestion, phosphopeptide enrichment and mass spectrometry analysis 19
XVII. Statistical analysis 20
Results 22
I. ZNF322A was a protein substrate of AKT 22
II. AKT interacted with ZNF322A 22
III. AKT upregulated ZNF322A protein expression in a transcription-independent manner 23
IV. AKT promoted ZNF322A protein stability 23
V. AKT enhanced ZNF322A transcriptional activity 24
VI. Phosphorylation-defective mutant T150A-, S224A-, T234A- or T262A- ZNF322A protein could not upregulate ADD1 and CCND1 mRNA expression 24
VII. ZNF322A Thr-262 phosphorylation promoted ZNF322A protein stability thus increased ZNF322A transcriptional activity 25
VIII. ZNF322A Thr-150 phosphorylation by AKT enhanced its transcriptional activity without affecting protein stability 26
IX. ZNF322A Ser-224 phosphorylation by AKT enhanced its transcriptional activity without affecting protein stability 27
X. ZNF322A Thr-234 phosphorylation by AKT enhanced its transcriptional activity without affecting protein stability 28
XI. Recruitment of ZNF322A transcriptional complex to promoter region of ADD1 and CCND1 28
XII. AKT promoted ZNF322A protein stability and transcription activity through EGF stimulation 29
XIII. ZNF322A phosphorylation by AKT enhanced lung cancer cell proliferation 30
XIV. AKT-mediated Thr-150, Ser-224, Thr-234 phosphorylation induced lung cancer cell migration 31
XV. AKT synergized with ZNF322A to accelerate tumor metastasis in vivo 32
XVI. Antibody specificity test of homemade p-S224 antibody in cell and clinical samples 32
Discussion 34
References 40
Tables 50
Figures 58
Appendix Figures 84

TABLE CONTENTS
Table 1. The vectors and their characteristics used in the current study 51
Table 2. The primers and their reaction conditions used in the current study 53
Table 3. The antibodies and their reaction conditions used in the current study 55
Table 4. Identification of ZNF322A phosphorylation sites and predicted kinases mass spectrometry analysis 56


FIGURE CONTENTS
Figure 1. ZNF322A was a protein substrate of AKT 59
Figure 2. AKT interacted with ZNF322A 60
Figure 3. AKT upregulated ZNF322A protein expression in a transcription-independent manner 61
Figure 4. AKT promoted ZNF322A protein stability 63
Figure 5. AKT enhanced ZNF322A transcriptional activity 64
Figure 6. Phosphorylation-defective mutant T150A-, S224A-, T234A- or T262A- ZNF322A protein could not upregulate ADD1 and CCND1 mRNA expression 65
Figure 7. ZNF322A Thr-262 phosphorylation promoted ZNF322A protein stability thus increased ZNF322A transcriptional activity 67
Figure 8. ZNF322A Thr-150 phosphorylation by AKT enhanced its transcriptional activity without affecting protein stability 69
Figure 9. ZNF322A Ser-224 phosphorylation by AKT enhanced its transcriptional activity without affecting protein stability 71
Figure 10. ZNF322A Thr-234 phosphorylation by AKT enhanced its transcriptional activity without protein stability 73
Figure 11. Recruitment of ZNF322A transcriptional complex to ADD1 and CCND1 promoter region 75
Figure 12. AKT promoted ZNF322A protein stability and transcriptional activity through EGF stimulation 77
Figure 13. ZNF322A phosphorylation by AKT enhanced lung cancer cell proliferation 79
Figure 14. AKT-mediated Thr150, Ser224, and Thr234 phosphorylation induced lung cancer cell migration 80
Figure 15. AKT synergized with ZNF322A to accelerate tumor metastasis in vivo 81
Figure 16 Antibody specificity test of homemade p-S224 antibody in cell and clinical samples 82
Figure 17. Schematic diagram of EGFR/AKT signaling axis pathway in promotion of ZNF322A protein stability and transcriptional activity in lung cancer 83

APPENDIX CONTENTS
Appendix Figure 1. AKT signaling pathway 85
Appendix Figure 2. Target therapy of AKT 86
Appendix Figure 3. AKT and GSK3 regulated ZNF322A protein expression through distinct signaling pathways 87
Appendix Figure 4. ZNF322A directly targeted to ADD1 AP1-2 element through zinc finger motifs 4th to 8th 88
Appendix Figure 5. Molecular modeling of the interaction between ZNF322A protein and DNA 89
Appendix Figure 6. ZNF322A formed homodimers 90
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