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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華 | |
| dc.contributor.author | Yu-Ru Lee | en |
| dc.contributor.author | 李育儒 | zh_TW |
| dc.date.accessioned | 2021-06-08T05:03:41Z | - |
| dc.date.copyright | 2011-03-03 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-02-25 | |
| dc.identifier.citation | Adams, J.M., and Cory, S. (1998). The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322-1326.
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Tor-mediated induction of autophagy via an Apg1 prote | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23538 | - |
| dc.description.abstract | 死亡相關蛋白激脢(DAPK)是一會受攜鈣素(calmodulin)所調控的serine/thronine死亡相關蛋白激脢。一開始DAPK被發現的原因是因為其會參與interferon所調控的細胞死亡。但至今，interferon如何活化DAPK，其間的機制仍不清楚。在本篇論文中，我們找到了KLHL20。它是一個含有BTB-Kelch功能區塊的蛋白。我們發現它會藉由與DAPK結合加速DAPK的本身的蛋白質降解。我們也找出其間的調控機制，那是KLHL20利用它的Kelch repeat與DAPK結合，再利用它的BTB功能區塊與Cullin3結合。而這樣一個由KLHL20-Cul3-ROC1組合而成的E3連接脢複合體我們也證實的確會促進DAPK的泛素化作用。我們更發現在interferon的刺激下，這樣一個訊號會減弱KLHL20對DAPK的泛素化作用。由於干擾素引發PML及PML nuclear body生成，KLHL20藉由與PML結合作用進入PML nuclear body，與DAPK分離，進而抑制DAPK蛋白降解作用。而此干擾素促進之DAPK穩定作用參與了干擾素引發之細胞凋亡及細胞自噬。此外，本論文以骨髓癌細胞模式，證實了干擾素抑制KLHL20對DAPK降解作用為骨髓癌細胞對干擾素敏感性之一項決定因子，因此對骨髓癌之治療策略上具重要參考價值。
除了死亡相關蛋白激脢，我們也發現KLHL20會在缺氧的情況下造成PML之反向調控。腫瘤缺氧與病情進展和治療失效有關，但缺氧的訊息機制並未完全明朗。在此，我們發現缺氧可透過HIF-1所誘發的KLHL20轉錄活化作用，由KLHL20扮演Cul3泛素接合酶之受質轉接蛋白，觸發泛素所媒介的PML腫瘤抑制蛋白之降解。然而，PML必需被CDK1/2於其S518位置進行磷酸化，才會被送至Cul3-KLHL20接合酶。我們證實由HIF-1所誘發、KLHL20所媒介的PML降解，以反饋機制充分地在缺氧情況下誘發HIF-1，進而強化缺氧所引起的代謝重整及上皮間質轉化現象。我們的研究找到一條涉及KLKL20、CDK1/2以及PML的HIF-1自我調控迴路，並提出此迴路對腫瘤進程之影響。 | zh_TW |
| dc.description.abstract | Death-associated protein kinase (DAPK) was identified as a mediator of interferon (IFN)-induced cell death. How IFN controls DAPK activation remains largely unknown. Here we identify the BTB-Kelch protein KLHL20 as a negative regulator of DAPK. KLHL20 binds DAPK and Cullin 3 (Cul3) via its Kelch-repeat domain and BTB domain, respectively. The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK. Accordingly, depletion of KLHL20 diminishes DAPK ubiquitination and degradation. The KLHL20-mediated DAPK ubiquitination is suppressed in cells receiving interferon (IFN) –α or IFN-γ, which induces an enrichment/sequestration of KLHL20 in the PML nuclear bodies, thereby separating KLHL20 from DAPK. Consequently, IFN triggers the stabilization of DAPK. This mechanism of DAPK stabilization is crucial for determining IFN responsiveness of tumor cells and contributes to IFN-induced autophagy. This study identifies KLHL20-Cul3-ROC1 as an E3 ligase for DAPK ubiquitination and reveals a regulatory mechanism of DAPK, through blocking its accessibility to this E3 ligase, in IFN-induced apoptotic and autophagic death. Our findings may be relevant to the problem of IFN resistance in cancer therapy.
Apart from DAPK, we also identify KLHL20 as a negative regulator of PML, and this regulation is controlled by hypoxia. Tumor hypoxia is associated with disease progression and treatment failure, but the hypoxia signaling mechanism is not fully understood. Here, we show that hypoxia triggers ubiquitin-dependent proteolysis of PML tumor suppressor through HIF-1-induced transactivation of KLHL20. Targeting PML to the Cul3-KLHL20 ligase, however, requires PML phosphorylation by CDK1/2 at S518. We present evidence indicating that this HIF-1-induced, KLHL20-mediated PML destruction participates in a feedback mechanism to maximize HIF-1 induction by hypoxia, thereby potentiating hypoxia-induced metabolic reprogramming and epithelial-mesenchymal transition. Our study identifies a HIF-1 autoregulatory loop involving KLHL20, CDK1/2 and PML and suggests a contribution of this loop to tumor progression. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T05:03:41Z (GMT). No. of bitstreams: 1 ntu-100-D94448006-1.pdf: 8626273 bytes, checksum: 030fec6117f7e3c1567442936d524c6a (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Table Contents 1
Abbreviations 9 中文摘要 11 Abstract 12 Literature Review 13 1. Apoptosis 13 1.1 Overview of apoptosis 13 1.2 Mitochondrial independent (extrinsic) apoptosis pathway 14 1.2.1 CD95L/CD95 (Fas) pathway 14 1.2.2 TNF/TNFR pathway 15 1.2.3 TRAIL/TRAILR pathway 16 1.3 Mitochondrial-associated (intrinsic) apoptosis pathway 16 1.4 The crosstalk between extrinsic and intrinsic apoptotic pathway 18 1.5 Anoikis-type apoptosis 18 2. Autophagy 19 2.1 Insights into autophagy 19 2.2 Autophagic mechanism 20 3. Interferon responses 22 3.1 The biological significance of IFNs signaling 22 3.1.1 Antiviral activities 22 3.1.1.1 The dsRNA-dependent protein kinase (PKR) pathway 23 3.1.1.2 The 2-5A system 23 3.1.1.3 The Mx pathway 23 3.1.2 Inhibition of Cell Growth 24 3.1.3 Control of apoptosis 24 3.2 The molecular mechanism of IFNs signaling 25 4. Hypoxia responses 26 4.1 The effects of hypoxia on cancer 26 4.2 Regulation of hypoxia-inducible factors (HIFs) by O2 availability 27 4.3 The role of HIFs in cancer 29 5. Ubiquitination 30 5.1 The cascade of ubiquitination 30 5.2 The diversity of E3 ubiquitin ligases 31 5.3 The multiple functions of ubiquitination 33 5.4 BTB-kelch proteins and KLHL20 (KLEIP) 34 5.4.1 BTB-kelch proteins 34 5.4.2 KLHL20 (KLEIP) 36 6. DAPK 36 6.1 DAPK family and the multi-domain structure of DAPK 36 6.2 DAPK in cell death 37 6.3 The tumor suppression function of DAPK 39 6.4 Regulation of DAPK 40 7. PML 41 7.1 The PML nuclear body and PML protein 41 7.2 PML function 43 7.2.1 Regulation of apoptosis 43 7.2.2 Regulation of cellular senescence 44 7.2.3 Regulation of angiogenesis 45 7.2.4 The function of cytoplasmic PML isoform 46 7.3 Regulation of PML expression and stability 46 Chapter I 49 The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses 49 Introduction 50 Results 52 KLHL20 forms a complex with Cul3 and DAPK 52 KLHL20-based Cul3 complex promotes DAPK ubiquitination in vitro and in vivo 54 KLHL20 promotes DAPK proteasomal degradation and attenuates its proapoptotic function. 55 IFN-α and IFN-γ inhibit KLHL20-dependent DAPK ubiquitination by sequestration of KLHL20 55 PML depletion reverses the inhibitory effect of IFN on DAPK ubiquitination and degradation. 57 DAPK stabilization by blocking KLHL20-mediated ubiquitination contributes to IFN-α-induced apoptosis in multiple myeloma (MM) cells. 58 Inhibition of KLHL20-mediated DAPK ubiquitination contributes to IFN-induced autophagy. 59 Discussion 60 Materials and Methods 63 Cell culture, transient transfection, and retroviral infection 63 Plasmids 64 Antibodies and reagents 64 Immunoprecipitation 65 Yeast two-hybrid screen 65 In vitro ubiquitination assay 65 Immunofluorescence analysis 65 Production of baculovirus 66 Apoptosis assay 66 Lentivirus production 66 Autophagy assay 67 Chapter II 68 A Cullin3-KLHL20 ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling 68 Introduction 69 Results 71 Hypoxia induces PML destabilization and KLHL20 transcription through HIF-1. 71 Cul3-KLHL20 ubiquitin ligase is responsible for PML ubiquitination 73 CDK1 and CDK2 phosphorylate PML S518 to promote KLHL20-mediated PML destruction. 74 S518 phosphorylation promotes the recruitment of PML to KLHL20 75 KLHL20-mediated PML destruction amplifies tumor hypoxia responses. 75 PML S518 phosphorylation is not required for the recruitment of KLHL20 to PML-NB. 76 Discussion 77 Materials and Methods 79 Plasmids 79 Antibodies and reagents 80 Cell culture, transfection, and establishment of stable cell lines 80 Lentivirus production and infection 81 Luciferase assay 81 qPCR analysis 81 ChIP assay 82 Kinase assay 82 Immunoprecipitation 83 In vitro and in vivo ubiquitination 83 Figures : 84 Fig.1 : Interaction of KLHL20 with DAPK. 84 Fig.2: Characterization of the anti-KLHL20 antiserum. 85 Fig3. DAPK interacts with KLHL20. 86 Fig. 4: Interaction of KLHL20 with Cul3 and DAPK. 87 Fig. 5: KLHL20 forms a complex with Cul3 and DAPK. 88 Fig. 6: KLHL20-based Cul3 complex promotes DAPK ubiquitination in vivo. 89 Fig. 7: Generation of a KLHL20 mutant that cannot bind Cul3. 90 Fig. 8: The DD of DAPK is important for DAPK ubiquitination by KLHL20-Cul3-ROC1 complex. 91 Fig. 9: Endogenous KLHL20 promotes DAPK ubiquitination. 92 Fig. 10: KLHL20-based Cul3 complex promotes DAPK ubiquitination in vitro. 93 Fig. 11: Purification of the KLHL20-based Cul3 complex by GST pull down analysis. 94 Fig. 12: KLHL20 promotes proteasomal degradation of DAPK. 95 Fig. 13: KLHL20 promotes DAPK turnover. 96 Fig. 14: Knockdown of KLHL20 increases DAPK steady-state level. 97 Fig. 15: KLHL20 inhibits the pro-apoptotic function of DAPK. 98 Fig. 16: IFN upregulates DAPK through inhibiting proteasomal degradation of DAPK. 99 Fig. 17: IFN blocks KLHL20-dependent DAPK ubiquitination. 100 Fig. 18: IFN does not affect the formation of ROC1-Cul3-KLHL20 complex. 101 Fig. 19: IFN blocks the interaction of KLHL20 with endogenous DAPK. 102 Fig. 20: IFN triggers the enrichment of KLHL20 in PML-NBs. 103 Fig. 21: IFN-α induces an enrichment of KLHL20 in PML-NBs. 104 Fig. 22: Interaction of KLHL20 with PML. 105 Fig. 23: DAPK and PML compete for binding KLHL20. 106 Fig. 24: Generation of PML knockdown cells. 107 Fig. 25: Depletion of PML abolishes IFN-γ-induced relocation of KLHL20 in PML-NBs. 108 Fig. 26: PML siRNA rescues the interaction between DAPK and KLHL20 in IFN-γ-treated cells. 109 Fig. 27: PML siRNA rescues KLHL20-mediated DAPK ubiquitination in IFN-γ-treated cells. 110 Fig. 28: IFN-γ fails to upregulate DAPK in PML null cells. 111 Fig. 29: PML is required for IFN-γ-induced DAPK stabilization. 112 Fig. 30: IFN-α induces PML-NBs and KLHL20 relocation in H929 cells but not in XG1 cells. 113 Fig. 31: IFN-α induces the disruption of KLHL20-DAPK complex in H929 cells but not in XG1 cells. 114 Fig. 32: IFN-α induces the upregulation of DAPK in H929 cells but not in XG1 cells. 115 Fig. 33: DAPK stabilization by blocking KLHL20-mediated ubiquitination contributes to IFN-α-induced apoptosis in multiple myeloma cells. 116 Fig. 34: Blockage of KLHL20-mediated DAPK degradation contributes to multiple myeloma cell responsiveness to IFN. 117 Fig. 35: IFN-γ treatment of MCF7 cells induces the concentration of KLHL20 to PML-NBs. 118 Fig. 36: Blockage of KLHL20-mediated DAPK degradation contributes to IFN-induced autophagy. 119 Fig. 37: Inhibition of KLHL20-mediated DAPK ubiquitination contributes to IFN-induced autophagy. 120 Fig. 38: IFN-induced autophagy is resulted from the increase in autophagosome formation rather than the blockage of lysosome-mediated autophagic flux. 121 Fig. 39: Models for the DAPK degradation pathway mediated by KLHL20-Cul3-ROC1 E3 ligase complex and for the inhibition of this pathway in IFN-treated cells. 122 Fig. 40: IFN-γ does not increase the amount of S308-phosphorylated DAPK. 123 Fig. 41: Hypoxia induces opposite regulations of PML and KLHL20. 124 Fig. 42: Hypoxia does not affect PML mRNA level. 125 Fig. 43: Hypoxia induces a downregulation of PML protein. 126 Fig. 44: Cycloheximide-chase experiment revealed an acceleration of PML protein turnover in response to hypoxia. 127 Fig. 45: Proteasome inhibitor MG132 triggered a greater PML upregulation in hypoxic than normoxic cells. 128 Fig. 46: Hypoxia promotes PML ubiquitination independent of its sumoylation. 129 Fig. 47: Regulation of KLHL20 by hypoxia. 130 Fig. 48: HIF-1α depletion by either of the two siRNAs blocked hypoxia-induced upregulation of KLHL20 and downregulation of PML. 131 Fig. 49: Schematic representations of the regulatory region of KLHL20 gene, the luciferase reporter constructs, and the ChIP primers used in this study. The positions of HREs and the sequences of wild type and mutant HREs are indicated. 132 Fig. 50: Mutation of either HRE reduced, and both HREs abolished the hypoxia or HIF-1α-induced KLHL20 promoter activity. 133 Fig. 51: KLHL20 interacts with PML endogenously. 134 Fig. 52: Knockdown of KLHL20 by two different siRNAs completely abrogated hypoxia-induced PML downregulation, whereas knockdown of RNF4 to a similar extent only slightly increased PML level in hypoxic cells. 135 Fig. 53: PML-I ubiquitination was downregulated drastically in hypoxic and moderately in normoxic cells by KLHL20 siRNA. 136 Fig. 54: In vitro ubiquitination of PML by KLHL20-Cul3-Roc1 complex. 137 Fig. 55: The pan-CDK inhibitor roscovitine blocked KLHL20-induced degradation of endogenous PML. 138 Fig. 56: Roscovitine blocks KLHL20-induced PML degradation. 139 Fig. 57: Roscovitine blocks KLHL20-induced PML ubiquitination. 140 Fig. 58: Dominant negative (DN) mutant of CDK1 or CDK2, but not CDK4 or CDK6, abrogated KLHL20-induced PML-I degradation. 141 Fig. 59: CDK phosphorylates PML at S518 in vitro. 142 Fig. 61: Overexpression of CDK1-cyclin B or CDK2-cyclin E enhanced S518 phosphorylation in vivo. 144 Fig. 62: The activities of CDK1 and CDK2 were not decreased by 24 h-treatment of hypoxia. 145 Fig. 63: The PML S518 phosphorylation level was not decreased by 24 h-treatment of hypoxia. 146 Fig. 64: S518 phosphorylation mediates PML interaction with KLHL20. 147 Fig. 65: S518 mutation impairs KLHL20-dependent PML ubiquitination. 148 Fig. 66: S518 mutation impairs KLHL20-induced PML degradation. 149 Fig. 67: PML S518A mutant is resistant to KLHL20-mediated degradation in hypoxic cells. 150 Fig. 68: Depletion of KLHL20 in PC3 cells led to an enhanced decline of mTOR activity (monitored by the phosphorylation of mTOR target S6 kinase) and a decreased induction of HIF-1α in response to hypoxia treatment. 151 Fig. 69: KLHL20-depleted cells exhibited a lower induction of HIF-1α targets VEGF (A) and GLUT1 (B) than control siRNA-expressing cells, and depletion of both KLHL20 and PML reversed these effects. 152 Fig. 70: EMT assays for cells cultured in normoxia or hypoxia for 24 h. 153 Fig .71: PML S518 phosphorylation is not required for the recruitment of KLHL20 to PML-NB. 154 Fig. 72: Scheme depicting the HIF-1α autoregulatory loop involving KLHL20, CDK, PML and mTOR. 155 Appendix 156 Appendix I: Regulation of KLHL20 and PML by HIF-1α. 156 Appendix II: Chromatin immunoprecipitation (ChIP) analysis confirmed the direct binding of HIF-1α to these KLHL20 regulating regions. 157 Appendix III: The specificity of the p518PML antibody. 158 Appendix IV: DN mutant of CDK1 or CDK2 blocked S518 phosphorylation in vivo. 159 Appendix V: Roscovitine or a CDK1/2 specific inhibitor blocked hypoxia-induced PML S518 phosphorylation and degradation. 160 Appendix VI: EMT assays for cells cultured in normoxia or hypoxia for 24 h. 161 References 162 | |
| dc.language.iso | en | |
| dc.title | 接合酶酵素KLHL20-Cul3-Roc1對抑癌蛋白DAPK及PML調控機制之探討 | zh_TW |
| dc.title | Regulation of the tumor suppressor proteins DAPK and
PML by KLHL20-Cul3-Roc1 ubiquitin E3 ligase | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 呂勝春,施修明,吳國瑞,張智芬 | |
| dc.subject.keyword | BTB區塊,Cullin3,死亡相關蛋白激脢,干擾素,PML nuclear bodies,缺氧,HIF-1α,KLHL20,CDK,PML, | zh_TW |
| dc.subject.keyword | BTB domain,Cullin3,DAPK,IFN,PML nuclear bodies,hypoxia,HIF-1α,KLHL20,CDK,PML, | en |
| dc.relation.page | 197 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2011-02-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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| ntu-100-1.pdf 未授權公開取用 | 8.42 MB | Adobe PDF |
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