進階搜尋


下載電子全文  
系統識別號 U0026-1907201711005400
論文名稱(中文) 探討轉譯後修飾作用對致癌鋅手指轉錄因子ZNF322A之調控機制
論文名稱(英文) Characterization of regulatory mechanism of oncogenic zinc finger transcription factor ZNF322A by post-translational modification
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 105
學期 2
出版年 106
研究生(中文) 廖昇佑
研究生(英文) Sheng-You Liao
學號 S58001438
學位類別 博士
語文別 英文
論文頁數 125頁
口試委員 指導教授-王憶卿
口試委員-賴明德
口試委員-洪建中
口試委員-林鼎晏
口試委員-陳瑞華
口試委員-徐駿森
中文關鍵字 肺癌  ZNF322A  CK1δ  GSK3β  FBXW7α  AKT  磷酸化  泛素化  蛋白質降解  轉錄活性 
英文關鍵字 lung cancer  ZNF322A  CK1δ  GSK3β  FBXW7α  AKT  phosphorylation  ubiquitination  protein degradation  transcriptional activity 
學科別分類
中文摘要 研究背景及目的: ZNF322A 為致癌轉錄調控因子,大約有70%的肺癌病人具有ZNF322A 過度表現及不良的預後。本實驗室先前利用細胞及動物模式證實 ZNF322A 能夠負向調控p53及正向調控adducin 1及cyclin D1的基因表現進而促進腫瘤生長及轉移侵襲能力。然而,目前對於ZNF322A 蛋白質過度表現及轉錄活性之調控機制仍不清楚。本篇研究主要探討蛋白質轉譯後修飾作用對於ZNF322A 蛋白質穩定度及轉錄活性之作用機制,並進一步研究其所調控之訊息傳遞路徑。
研究結果: 本研究先經由整合蛋白質體學及蛋白質磷酸化資料庫分析,發現許多ZNF322A 磷酸化位點,經由分析軟體預測 GSK3β及AKT可能為ZNF322A蛋白質激酶。進一步以試管內激酶反應 (in vitro kinase assay) 及細胞泛素化分析 (cell-based ubiquitination assay),我們發現CK1δ/GSK3β/FBXW7α訊息路徑能夠促進ZNF322A致癌蛋白降解。CK1δ及GSK3β能夠分別依續在ZNF322A Ser-396 及 Ser-391進行磷酸化,磷酸化態ZNF322A能夠受到FBXW7α泛素E3連結酶辨認,進而促進ZNF322A 蛋白降解。細胞及動物實驗確認FBXW7α過度表現促進ZNF322A蛋白降解進而抑制ZNF322A轉錄活性及ZNF322A所誘導之細胞生長的轉移能力。進一步,經由臨床檢體分析發現肺癌病人過度表達ZNF322A與FBXW7α 低表達或CK1δ/GSK3β之磷酸化作用之缺陷相關且病人具有較差的預後;此外,多變項Cox迴歸分析顯示,過度表達ZNF322A與低表達FBXW7α之組合可作為肺癌病人的死亡危險及預後指標。除此之外,我們也發現AKT能夠磷酸化ZNF322A進而促進ZNF322A 蛋白質穩定度及轉錄活性。AKT 調控ZNF322A Thr-262位點磷酸化,增加ZNF322A 蛋白穩定度進而促進其轉錄活性;此外,ZNF322A Thr-150、Ser-24及Thr-234受到AKT磷酸化後能夠增加ZNF322A結合DNA之親和力進而促進ZNF322A轉錄活性及正向調控adducin 1之基因表現。以上研究結果顯示AKT為ZNF322A 的正向調節者促進ZNF322A蛋白活性。
研究結論: 本研究提供了新穎的作用機制揭示CK1δ/GSK3β/FBXW7α訊息路徑調控ZNF322A致癌蛋白之降解作用;此外,本研究發現AKT能夠增加ZNF322A 致癌蛋白穩定度並促進其轉錄活性。我們預期透過標靶藥物促進CK1δ/GSK3β/FBXW7α誘導ZNF322A蛋白降解或抑制AKT訊息路徑可作為肺癌治療之新策略。
英文摘要 Background and Study purpose: Overexpression of oncogenic transcription factor ZNF322A is found in about 70% lung cancer patients with poor prognosis. We previous demonstrated that ZNF332A negatively regulates p53 expression and positively regulates expression of adducin 1 and cyclin D1 thus promotes lung cancer growth and metastasis. However, the regulatory mechanisms of ZNF322A overexpression and transcriptional activity remain poorly understood. Therefore, this study aims to investigate the post-translational modifications on ZNF322A protein stability control and transcriptional activity associated with its oncogenic effects in lung cancer.
Results: We identified several ZNF322A phosphorylation sites by integrating our proteomic analysis and online database data. GSK3β and AKT are predicted to be the putative protein kinases of ZNF322A. We further confirmed that CK1δ/GSK3β/FBXW7α signaling axis promoted protein degradation of ZNF322A oncoprotein using in vitro kinase assay and cell-based ubiquitination assay. CK1δ and GSK3β sequentially phosphorylated ZNF322A at Ser-396 and then Ser-391, the doubly phosphorylated ZNF322A protein were recognized by ubiquitin ligase FBXW7α leading to ZNF322A protein destruction. Overexpression of FBXW7α induced ZNF322A protein degradation, thereby blocked ZNF322A transcription activity and suppressed ZNF322A-induced tumor growth and metastasis in vitro and in vivo. Clinically, overexpression of ZNF322A correlated with low FBXW7α or defective CK1δ/GSK3β-mediated phosphorylation in lung cancer patients with poor prognosis. Multivariate Cox regression analysis indicated that patients with ZNF322A-high/FBXW7-low expression profile could be used as an independent factor to predict the clinical outcome in lung cancer patients. In addition, we identified that AKT phosphorylated ZNF322A thus promoted ZNF322A protein stability and transcriptional activity. AKT-mediated ZNF322A phosphorylation at Thr-262 enhanced ZNF322A protein stability thus promoted ZNF322A transcriptional activity. Moreover, ZNF322A Thr-150, Ser-224 and Thr-234 phosphorylation by AKT promoted ZNF322A transcriptional activity through increasing chromatin DNA binding affinity of ZNF322A thereby up-regulated adducin 1 mRNA expression. These results indicated that AKT served as the positive regulator of ZNF322A via promoting ZNF322A protein stability and transcriptional activity.
Conclusion: Our studies provide the novel mechanism of CK1δ/GSK3β/FBXW7α signaling axis in regulation of ZNF322A protein degradation. Moreover, AKT positively regulates ZNF322A oncoprotein protein stability and transcriptional activity. We propose that therapeutic strategies targeting ZNF322A oncoprotein for degradation by promoting CK1δ/GSK3β/FBXW7α signaling axis or inhibiting AKT signaling may provide new insight of target therapy for lung cancer patients.
論文目次 中文摘要 I
ABSTRACT III
誌謝 V
INTRODUCTION 1
1. Lung cancer
1-1. Clinical signification of lung cancer 1
1-2. Therapeutic strategies of lung cancer 1
2. Zinc finger (ZNF) transcription factor
2-1. Overview of ZNF transcription factor 2
2-2. Role of ZNF transcription factor in cancer 3
2-3. Previous studies of ZNF322A 4
3. Post-translational modification (PTM) of transcription factor
3-1. Role of PTM in regulating protein stability of transcription factor 5
3-2. Role of PTM in regulating transcriptional activity of transcription factor 6
4. Role of protein kinases in regulation of transcription factor
4-1. Glycogen synthase kinase 3 beta (GSK3β) 7
4-2. Casein kinase 1 (CK1) 8
4-3. AKT 9
5. Ubiquitination-mediated protein degradation
5-1. Introduction of ubiquitin proteasome system 10
5-2. SCF type E3 ubiquitin ligase FBXW7 10
STUDY BASIS AND DESIGN 12
MATERIALS AND METHODS 14
1. Patient samples and clinical information 14
2. Cell lines and culture conditions 14
3. Immunohistochemistry assay 14
4. Plasmid transfection and generation of stable knockdown cell lines 15
5. Reagents 15
6. Immunoblotting and immunoprecipitation 16
7. Cloning, expression and purification of the
human ZNF322A recombinant protein 16
8. Site-directed mutagenesis 17
9. RNA extraction and quantitative reverse-transcriptase
polymerase chain reaction (RT-qPCR) assays 18
10. Cycloheximide chase assay 18
11. In vitro kinase assay 18
12. Mass spectrometry analysis 19
13. Cell-based ubiquitination assay 20
14. Dual luciferase promoter assay 21
15. Chromatin-immunoprecipitation (ChIP)-qPCR assay 21
16. Cell migration and invasion assay 21
17. Cell proliferation assay 22
18. Anchorage-independent growth assay 22
19. In vivo tumor growth assay 22
20. In vivo tumor metastasis assay 23
21. Statistic analysis 23
RESULTS 24
PART I: Regulation of ZNF322A protein degradation by CK1δ/GSK3β/FBXW7α axis
1. Phosphoproteomic analyses reveal candidate ZNF322A phosphorylation sites 24
2. ZNF322A is a short half-life protein regulated
by ubiquitin-proteasome system 24
3. Ser-396 is the main phosphorylation site of CK1δ
in regulating ZNF322A protein stability 25
4. Phosphorylation of ZNF322A by CK1δ triggers
the subsequent phosphorylation by GSK3β 26
5. CK1δ regulates ZNF322A protein stability 27
6. GSK3β regulates ZNF322A protein stability 28
7. Phosphorylation of ZNF322A at Ser-396 and Ser-391 by CK1δ and GSK3β
is crucial for ZNF322A protein degradation 28
8. CK1δ-mediated ZNF322A phosphorylation at Ser-396 was required for
targeting of ZNF322A protein by GSK3β 29
9. FBXW7α is an E3 ligase targeting ZNF322A protein
for ubiquitination and degradation 31
10. Phosphorylation of Ser-391 and Ser-396 facilitates the recognition
and degradation of ZNF322A by FBXW7α 32
11. The CK1δ/GSK3β/FBXW7α axis regulates ZNF322A protein stability and inhibits ZNF322A-induced transcriptional activity, cell proliferation and motility 33
12. CK1δ/GSK3β/FBXW7α axis is inactivated in a sub-group of lung cancer patients
and correlates with ZNF322A overexpression and poor prognosis 34
13. Etoposide induced ZNF322A protein destruction
in CK1δ/GSK3β-dependent manner 36
Part II study: Regulation of ZNF322A transcriptional activity by AKT
1. ZNF322A is a protein substrate of AKT 37
2. AKT enhances ZNF322A protein stability 37
3. AKT promotes ZNF322A transcriptional activity 39
4. ZNF322A Thr-262 phosphorylation by AKT promotes ZNF322A protein stability
thus increases ZNF322A transcriptional activity 40
5. AKT phosphorylates ZNF322A at Thr-150, Ser-224, Thr-234 sites
to enhance ZNF322A transcriptional activity 41
6. AKT phosphorylates ZNF322A at Thr-150, Ser-224, Thr-234 sites
to increase DNA binding affinity of ZNF322A 41
DISCUSSION 43
REFERENCES 50
TABLES 62
FIGURES 78
APPENDIX 122


TABLE CONTENTS
Table 1. The clinicopathological parameters of 135 lung cancer patients
enrolled in this study 63
Table 2. Antibodies and their reaction conditions used
in the current study 64
Table 3. The plasmids and their characteristics used
in the current study 67
Table 4. The sh-RNA plasmids and their characteristics used
in the current study 71
Table 5. The primers used in the current study 72
Table 6. Identification of ZNF322A phosphorylation sites and predicted kinases 74
Table 7. Alteration of ZNF322A and FBXW7 protein expression levels in relation to clinicopathological parameters in 135 Lung Cancer Patients 75
Table 8. Cox regression analysis of risk factors for cancer-related death
in lung cancer patients 76
Table 9. Identification of AKT-mediated ZNF322A phosphorylation sites 77

FIGURE CONTENTS
Figure 1. ZNF322A is a highly unstable protein regulated
by ubiquitin-proteasome system 79
Figure 2. CK1δ isoform regulates ZNF322A protein expression 81
Figure 3. Ser-396 is the main phosphorylation site of CK1δ
in regulating ZNF322A protein stability 82
Figure 4. Priming phosphorylation of ZNF322A at Ser-396 by CK1δ is required for
GSK3β-mediated phosphorylation of ZNF322A at Ser-391 in vitro 83
Figure 5. CK1δ regulates ZNF322A protein expression in PTM dependent manner 84
Figure 6. CK1δ promotes ZNF322A protein ubiquitination 85
Figure 7. GSK3β regulates ZNF322A protein expression in PTM dependent manner 86
Figure 8. GSK3β promotes ZNF322A protein ubiquitination 87
Figure 9. ZNF322A phosphorylation defective mutant S391A-, S396A-
and S391A/396A protein exhibit longer protein half-life 88
Figure 10. Antibody specificity of homemade p-Ser-391 and p-Ser-396 antibodies 89
Figure 11. GSK3β and CK1δ phosphorylate ZNF322A at Ser-391 and Ser-396
promotes ZNF322A protein destruction 90
Figure 12. ZNF322A Ser-396 phosphorylation by CK1δ is required for
GSK3β-mediated ZNF322A protein degradation 91
Figure 13. Both CK1δ and GSK3β are crucial for ZNF322A protein destruction 92
Figure 14. FBXW7α is an E3 ubiquitin ligase of ZNF322A 93
Figure 15. FBXW7α promotes ZNF322A protein ubiquitination and degradation 94
Figure 16. FBXW7α promotes ZNF322A ubiquitination and degradation
in CK1δ/GSK3β dependent manner 96
Figure 17. ZNF322A Ser-391 and Ser-396 phosphorylation is crucial for
FBXW7α-mediated ZNF322A protein degradation 97
Figure 18. FBXW7α overexpression decreases ZNF322A transcriptional activity 98
Figure 19. Overexpression of CK1δ and GSK3β suppress
ZNF322A-induced lung cancer cell proliferation and motility 99
Figure 20. FBXW7α impairs ZNF322A-induced lung cancer cell proliferation 100
Figure 21. FBXW7α impairs ZNF322A-induced lung cancer cell motility 101
Figure 22. FBXW7α abolishes ZNF322A-induced lung tumor growth and metastasis 102
Figure 23. The reverse correlation between ZNF322A and FBXW7 expression
was observed in lung cancer patients 103
Figure 24. Low FBXW7α expression correlates with ZNF322A overexpression
and poor prognosis 104
Figure 25. The reverse correlation between ZNF322A and p-S391expression
was observed in a sub-group of lung cancer patients 105
Figure 26. Etoposide induced ZNF322A protein destruction
in CK1δ- and GSK3β-dependent manner 106
Figure 27. ZNF322A is a protein substrate of AKT 107
Figure 28. AKT interacts with ZNF322A in lung cancer cells 108
Figure 29. AKT regulates ZNF322A protein expression
in transcriptional independent manner 109
Figure 30. AKT enhances ZNF322A protein stability 110
Figure 31. EGF stimulation activates AKT and stabilizes ZNF322A protein
by partially inhibiting GSK3β activity. 111
Figure 32. AKT promotes ZNF322A transcriptional activity 112
Figure 33. EGF stimulation promotes ZNF322A transcriptional activity 113
Figure 34. Protein expression level of various ZNF322A phospho-mutants 114
Figure 35. ZNF322A Thr-150, Ser-224, and Thr-234 phosphorylation sites
do not affect ZNF322A protein stability 115
Figure 36. ZNF322A Thr-262 phosphorylation by AKT promotes ZNF322A protein stability thus increases ZNF322A transcriptional activity 116
Figure 37. AKT-mediated ZNF322A phosphorylation at Thr-150, Ser-224, Thr-234
enhances ZNF322A transcriptional activity 117
Figure 38. Phosphorylation-defective mutant T150A-, S224A-, T234A- or T262A-
ZNF322A protein cannot upregulate ADD1 mRNA expression 118
Figure 39. ZNF322A Thr-150, Ser-224, and Thr-234 phosphorylation sites
affect DNA binding affinity of ZNF322A 119
Figure 40. Schematic diagram of CK1δ/GSK3β/FBXW7α signaling axis and EGFR/AKT signaling axis in regulation of ZNF322A protein stability and activity. 120
Figure 41. Molecule modeling of the interaction between
ZNF322A protein and DNA 121

Appendix Figures
Appendix Figure 1. Identification of ZNF322A Ser-391 phosphorylation
by mass spectrometry analysis 123
Appendix Figure 2. Identification of AKT-mediated ZNF322A phosphorylation sites
by mass spectrometry analysis 124
PUBLICATION 125

參考文獻 Abildgaard MO, Borre M, Mortensen MM, Ulhøi BP, Tørring N, Wild P, Kristensen H, Mansilla F, Ottosen PD, Dyrskjøt L, Ørntoft TF, Sørensen KD. (2012). Downregulation of zinc finger protein 132 in prostate cancer is associated with aberrant promoter hypermethylation and poor prognosis. Int J Cancer. 130(4):885-95.
Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, Cepeda D, Fiegl H, Dafou D, Marth C, Mueller-Holzner E, Corcoran M, Dagnell M, Nejad SZ, Nayer BN, Zali MR, Hansson J, Egyhazi S, Petersson F, Sangfelt P, Nordgren H, Grander D, Reed SI, Widschwendter M, Sangfelt O, Spruck C. (2007). FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 67(19):9006-12.
Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, Unger M, Testa JR. (2004). Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis. 25: 2053-2059.
Bullen JW, Tchernyshyov I, Holewinski RJ, DeVine L, Wu F, Venkatraman V, Kass DL, Cole RN, Van Eyk J, Semenza GL. (2016). Protein kinase A-dependent phosphorylation stimulates the transcriptional activity of hypoxia-inducible factor 1. Sci Signal. 9(430):ra56.
Busino L, Millman SE, Scotto L, Kyratsous CA, Basrur V, O'Connor O, Hoffmann A, Elenitoba-Johnson KS, Pagano M. (2012). Fbxw7alpha- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma. Nat Cell Biol. 14(4):375-85.
Carpenter RL, Paw I, Dewhirst MW, Lo HW. (2015). Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells. Oncogene. 34(5): 546–557.
Cheong JK, Virshup DM. (2011). Casein kinase 1: Complexity in the family. Int J Biochem Cell Biol. 43(4):465-9.
Cho JG, Park S, Lim CH, Kim HS, Song SY, Roh TY, Sung JH, Suh W, Ham SJ, Lim KH, Park SG. (2016). ZNF224, Krüppel like zinc finger protein, induces cell growth and apoptosis-resistance by down-regulation of p21 and p53 via miR-663a. Oncotarget. 7(21):31177-90.
Cohen P, and Frame S. (2001). The renaissance of GSK3. Nat Rev Mol Cell Biol. 2(10):769-76.
David O, Jett J, LeBeau H, Dy G, Hughes J, Friedman M, Brody AR. (2004). Phospho-Akt overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage. Clin Cancer Res. 10:6865-71.
Davis RJ, Welcker M, Clurman B. Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer Cell 2014; 26: 455-64.
Dempke WC, Suto T, Reck M. (2010). Targeted therapies for non-small cell lung cancer. Lung Cancer. 67(3):257-74.
Doble BW and Woodgett JR. (2003). GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 116(Pt 7):1175-86.
Fang L, Zhang L, Wei W, Jin X, Wang P, Tong Y, Li J, Du JX, Wong J. (2014). A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation. Mol Cell. 55(4):537-51.
Filtz TM, Vogel WK, Leid M. (2014). Regulation of transcription factor activity by interconnected post-translational modifications. Trends Pharmacol Sci. 35(2):76-85.
Gamper AM, Qiao X, Kim J, Zhang L, DeSimone MC, Rathmell WK, Wan Y. (2012). Regulation of KLF4 turnover reveals an unexpected tissue-specific role of pVHL in tumorigenesis. Mol Cell. 45(2):233-43.
Gamsjaeger R, Liew CK, Loughlin FE, Crossley M, Mackay JP. (2007). Sticky fingers: zinc-fingers as protein-recognition motifs. Trends Biochem Sci. 32(2):63-70.
Gan W, Dai X, Lunardi A, Li Z, Inuzuka H, Liu P, Varmeh S, Zhang J, Cheng L, Sun Y, Asara JM, Beck AH, Huang J, Pandolfi PP, Wei W. (2015). SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression. Mol Cell. 59(6):917-30.
Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W. (2009). Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol. 11(4):397-408.
Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas GV, Dai MS, Qian DZ. (2012). HIF1α protein stability is increased by acetylation at lysine 709. J Biol Chem. 287(42):35496-505.
Giaccia AJ, and KastanMB. (1998). The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12(19):2973-83.
Gregory MA and Hann SR. (2000). c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol Cell Biol. 20(7):2423-35.
Hao B, Oehlmann S, Sowa ME, Harper JW, Pavletich NP. (2007). Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Mol Cell. 26(1):131-43.
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 4(12):988-1004.
Hergovich A, Lisztwan J, Thoma CR, Wirbelauer C, Barry RE, Krek W. (2006). Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3. Mol Cell Biol. 26(15):5784-96.
Herbst RS, Heymach JV, Lippman SM. (2008). Lung cancer. N Engl J Med. 359: 1367-1380.
Hoeller D, Hecker CM, Dikic I. (2006). Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer. 6(10):776-88.
Hong J, Zhou J, Fu J, He T, Qin J, Wang L, Liao L, Xu J. (2011). Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 71(11):3980-90.
Hsu DS, Wang HJ, Tai SK, Chou CH, Hsieh CH, Chiu PH, Chen NJ, Yang MH. (2014). Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages. Cancer Cell. 26(4):534-48.
Hu CW, Hsu CL, Wang YC, Ishihama Y, Ku WC, Huang HC, Juan HF. (2015). Temporal phosphoproteome dynamics induced by an ATP synthase inhibitor Citreoviridin. Mol Cell Proteomics. 14: 3284-98.
Huang WC, Chen CC. (2005). Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. Mol Cell Biol. 25: 6592-6602.
Inuzuka H, Tseng A, Gao D, Zhai B, Zhang Q, Shaik S, Wan L, Ang XL, Mock C, Yin H, Stommel JM, Gygi S, Lahav G, Asara J, Xiao ZX, Kaelin WG Jr, Harper JW, Wei W. (2010). Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell. 18(2):147-59.
Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W. (2011). SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature.;471(7336):104-9.
Jen J, Lin LL, Chen HT, Liao SY, Lo FY, Tang YA, Su WC, Salgia R, Hsu CL, Huang HC, Juan HF, Wang YC. (2016). Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer. Oncogene. 35(18):2357-69.
Jia D, Hasso SM, Chan J, Filingeri D, D'Amore PA, Rice L, Pampo C, Siemann DW, Zurakowski D, Rodig SJ, Moses MA. (2013). Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo. Blood. 121(4):707-15.
Kang T, Wei Y, Honaker Y, Yamaguchi H, Appella E, Hung MC, Piwnica-Worms H. (2008). GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Cancer Cell. 13(1):36-47.
Kao SH, Wang WL, Chen CY, Chang YL, Wu YY, Wang YT, Wang SP, Nesvizhskii AI, Chen YJ, Hong TM, Yang PC. (2013). GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug. Oncogene. 33(24):3172-82.
Knippschild U, Krüger M, Richter J, Xu P, García-Reyes B, Peifer C, Halekotte J, Bakulev V, Bischof J. (2014). The CK1 family: contribution to cellular stress response and its role in carcinogenesis. Front Oncol. 4:96
Kulikov R, Winter M, Blattner C. (2006). Binding of p53 to the central domain of Mdm2 is regulated by phosphorylation. J Biol Chem. 281: 28575-28583.
Laity JH, Lee BM, Wright PE. (2001). Zinc finger proteins: new insights into structural and functional diversity. Curr Opin Struct Biol. 11(1):39-46.
Langer CJ, Besse B, Gualberto A, Brambilla E, Soria JC. (2010). The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol. 28(36):5311-20.
Lee WP, Lan KH, Li CP, Chao Y, Lin HC, Lee SD. (2016). Akt phosphorylates myc-associated zinc finger protein (MAZ), releases P-MAZ from the p53 promoter, and activates p53 transcription. Cancer Lett. 375(1):9-19.
Li Y, Wang Y, Zhang C, Yuan W, Wang J, Zhu C, Chen L, Huang W, Zeng W, Wu X, Liu M. (2004). ZNF322, a novel human C2H2 Kruppel-like zinc-finger protein, regulates transcriptional activation in MAPK signaling pathways. Biochem Biophys Res Commun. 325(4):1383-92.
Lin Y, Yang Y, Li W, Chen Q, Li J, Pan X, Zhou L, Liu C, Chen C, He J, Cao H, Yao H, Zheng L, Xu X, Xia Z, Ren J, Xiao L, Li L, Shen B, Zhou H, Wang YJ. (2012). Reciprocal regulation of Akt and Oct4 promotes the self-renewal and survival of embryonal carcinoma cells. Mol Cell. 48: 627-640.
Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X. (2002). Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 108(6):837-47.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 350(21):2129-39.
Ma H, Ng HM, Teh X, Li H, Lee YH, Chong YM, Loh YH, Collins JJ, Feng B, Yang H, Wu Q. (2014). Zfp322a Regulates mouse ES cell pluripotency and enhances reprogramming efficiency. PLoS Genet. 10(2):e1004038.
Ma X, Huang M, Wang Z, Liu B, Zhu Z, Li C. (2016). ZHX1 Inhibits Gastric Cancer Cell Growth through Inducing Cell-Cycle Arrest and Apoptosis. J Cancer. 7(1):60-8.
Marin O, Bustos VH, Cesaro L, Meggio F, Pagano MA, Antonelli M, Allende CC, Pinna LA, Allende JE. (2003). A noncanonical sequence phosphorylated by casein kinase 1 in beta-catenin may play a role in casein kinase 1 targeting of important signaling proteins. Proc Natl Acad Sci U S A. 100:10193-200.
McCarty AS, Kleiger G, Eisenberg D, Smale ST. (2013). Selective dimerization of a C2H2 zinc finger subfamily. Mol Cell. 11(2):459-70.
Nakayama KI and Nakayama K. (2006). Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 6(5):369-81.
Persikov AV, Wetzel JL, Rowland EF, Oakes BL, Xu DJ, Singh M, Noyes MB. (2015).A systematic survey of the Cys2His2 zinc finger DNA-binding landscape. Nucleic Acids Res. 43(3):1965-84.
Pontano LL, Aggarwal P, Barbash O, Brown EJ, Bassing CH, Diehl JA (2008). Genotoxic stress-induced cyclin D1 phosphorylation and proteolysis are required for genomic stability. Molecular and cellular biology 28: 7245-7258.
Ramalingam S, Belani C. (2008). Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 13 Suppl 1:5-13.
Rappsilber J, Mann M, Ishihama Y. (2007). Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc. 2: 1896-906.
Razin SV, Borunova VV, Maksimenko OG, Kantidze OL. (2012) Cys2His2 zinc finger protein family: classification, functions, and major members. Biochemistry (Mosc). 77(3):217-26.
Sakaguchi K, Saito S, Higashimoto Y, Roy S, Anderson CW, Appella E. (2000). Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem. 275(13):9278-83.
Sant, M., Allemani, C., Santaquilani, M., Knijn, A., Marchesi, F., and Capocaccia, R. (2009). EUROCARE-4. Survival of cancer patients diagnosed in 1995-1999. Results and commentary. Eur J Cancer. 45, 931-991.
Sato N, Kawai T, Sugiyama K, Muromoto R, Imoto S, Sekine Y, Ishida M, Akira S, Matsuda T. (2005). Physical and functional interactions between STAT3 and ZIP kinase. Int Immunol. 17(12):1543-52.
Schaefer T, Wang H, Mir P, Konantz M, Pereboom TC, Paczulla AM, Merz B, Fehm T, Perner S, Rothfuss OC, Kanz L, Schulze-Osthoff K, Lengerke C. (2015). Molecular and functional interactions between AKT and SOX2 in breast carcinoma. Oncotarget. 6(41):43540-56.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. (2002). Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 346(2):92-8.
Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PC. (2014). A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 9(2):154-62.
Siegel RL, Miller KD, Jemal A. (2016). Cancer statistics, 2016. CA Cancer J Clin. 66(1):7-30.
Skaar JR, Pagan JK, Pagano M. (2013). Mechanisms and function of substrate recruitment by F-box proteins. Nat Rev Mol Cell Biol.14: 369-81.
Skaar JR, Pagan JK, Pagano M. (2014).SCF ubiquitin ligase-targeted therapies.Nat Rev Drug Discov. 13(12):889-903.
Steuer CE, Khuri FR, Ramalingam SS.(2015). The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer. Cancer. 121(8):E1-6.
Steuer CE, Ramalingam SS. (2015).Targeting EGFR in lung cancer: Lessons learned and future perspectives. Mol Aspects Med. 45:67-73.
Sugiyama N, Masuda T, Shinoda K, Nakamura A, Tomita M, Ishihama Y. (2007). Phosphopeptide enrichment by aliphatic hydroxy acid-modified metal oxide chromatography for nano-LC-MS/MS in proteomics applications. Mol Cell Proteomics. 6: 1103-09.
Tang JM, He QY, Guo RX, Chang XJ. (2006). Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 51(2):181-91.
Thollet A, Vendrell JA, Payen L, Ghayad SE, Ben Larbi S, Grisard E, Collins C, Villedieu M, Cohen PA. (2010). ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells. Mol Cancer. 9:291.
Uckun FM, Ma H, Zhang J, Ozer Z, Dovat S, Mao C, Ishkhanian R, Goodman P, Qazi S. (2012). Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros. Proc Natl Acad Sci U S A. 109(44):18072-7.
Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM. (2009). A census of human transcription factors: function, expression and evolution. Nat Rev Genet. 10(4):252-63.
Vendrell JA, Thollet A, Nguyen NT, Ghayad SE, Vinot S, Bièche I, Grisard E, Josserand V, Coll JL, Roux P, Corbo L, Treilleux I, Rimokh R, Cohen PA. (2012). ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion. Cancer Res. 72(14):3593-606.
Vivanco I1, Sawyers CL. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2(7):489-501.
Wang R, Wang Y, Liu N, Ren C, Jiang C, Zhang K, Yu S, Chen Y, Tang H, Deng Q, Fu C, Wang Y, Li R, Liu M, Pan W, Wang P. (2013). FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation. Cell Res. 23(6):803-19.
Wang X and Zhao J. (2007). KLF8 transcription factor participates in oncogenic transformation. Oncogene. 26(3):456-61.
Wang Z, Liu P, Inuzuka H, Wei W. (2014). Roles of F-box proteins in cancer. Nat Rev Cancer.14: 233-47.
Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG Jr. (2005). The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell. 8(1):25-33.
Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, Clurman BE. (2004). The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A. 101(24):9085-90.
Welcker M, and Clurman BE. (2008). FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 8(2):83-93.
Werden SJ, Sphyris N, Sarkar TR, Paranjape AN, LaBaff AM, Taube JH, Hollier BG, Ramirez-Peña EQ, Soundararajan R, den Hollander P, Powell E, Echeverria GV, Miura N, Chang JT, Piwnica-Worms H, Rosen JM, Mani SA. (2016). Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth. Oncogene. 35(46):5977-5988.
Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, Belmont LD, Kaminker JS, O'Rourke KM, Pujara K, Kohli PB, Johnson AR, Chiu ML, Lill JR, Jackson PK, Fairbrother WJ, Seshagiri S, Ludlam MJ, Leong KG, Dueber EC, Maecker H, Huang DC, Dixit VM. (2011). Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 471: 110-4.
Wolfe SA, Nekludova L, Pabo CO. (2000). DNA recognition by Cys2His2 zinc finger proteins. Annu Rev Biophys Biomol Struct. 29:183-212.
Xu C, Kim NG, Gumbiner BM. (2009). Regulation of protein stability by GSK3 mediated phosphorylation. Cell Cycle. 8(24):4032-9.
Xu Y, Lee SH, Kim HS, Kim NH, Piao S, Park SH, Jung YS, Yook JI, Park BJ, Ha NC. (2010). Role of CK1 in GSK3beta-mediated phosphorylation and degradation of snail. Oncogene. 29(21):3124-33.
Yip PY, Cooper WA, Kohonen-Corish MR, Lin BP, McCaughan BC, Boyer MJ, Kench JG, Horvath LG. (2014). Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer. J Clin Pathol. 67(4):333-40.
Yokobori T, Yokoyama Y, Mogi A, Endoh H, Altan B, Kosaka T, Yamaki E, Yajima T, Tomizawa K, Azuma Y, Onozato R, Miyazaki T, Tanaka S, Kuwano H. (2014). FBXW7 mediates chemotherapeutic sensitivity and prognosis in NSCLCs. Mol Cancer Res. 12(1):32-7.
Yu J, Liang QY, Wang J, Cheng Y, Wang S, Poon TC, Go MY, Tao Q, Chang Z, Sung JJ. (2013a). Zinc-finger protein 331, a novel putative tumor suppressor, suppresses growth and invasiveness of gastric cancer. Oncogene. 32(3):307-17.
Yu HG, Wei W, Xia LH, Han WL, Zhao P, Wu SJ, Li WD, Chen W.. (2013b). FBW7 upregulation enhances cisplatin cytotoxicity in non- small cell lung cancer cells. Asian Pac J Cancer Prev. 14(11):6321-6.
Zhao B, Li L, Tumaneng K, Wang CY, Guan KL. (2010a). A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 24(1):72-85.
Zhao D, Zheng HQ, Zhou Z, Chen C. (2010b). The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses breast cell proliferation. Cancer Res. 70(11):4728-38.
Zheng H, Shen M, Zha YL, Li W, Wei Y, Blanco MA, Ren G, Zhou T, Storz P, Wang HY, Kang Y. (2014). PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. Cancer Cell. 26(3):358-73.
Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. (2004). Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 6(10):931-40.
Zhou H, Liu Y, Zhu R, Ding F, Wan Y, Li Y, Liu Z. (2017). FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation. Oncogene. doi: 10.1038/onc.2016.479. [Epub ahead of print]
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2019-08-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2019-08-01起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw