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研究生:楊聿智
研究生(外文):Yi-Chin Yang
論文名稱:Daxx的進核訊息位置之判別
論文名稱(外文):Identification of the NLS and NES of Daxx
指導教授:陳和瑟陳和瑟引用關係
指導教授(外文):Angela Chen
學位類別:碩士
校院名稱:國立中山大學
系所名稱:生物醫學科學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:139
中文關鍵詞:出核訊息入核訊息
外文關鍵詞:Daxxnuclear localization signalSUMOsumoylationnuclear export signal
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SUMO是small ubiquitin-like modifier,而Daxx是Fas death-domain association protein,在一般的情況之下,SUMO與Daxx主要是存在於核內的。將SUMO與紅色螢光蛋白形成融合蛋白送進細胞中,active SUMO(可進行sumoylatoin)會進核內並形成nuclear bodies,而inactive SUMO(無sumoylation的能力)會散佈在細胞質中。Daxx是SUMO的目標蛋白之一,也是組成POD的蛋白,當有外界的壓力且有Ask1存在之下,Daxx會跑到細胞質中,因此,Daxx應該是一個shuttle protein,它應該擁有nuclear localization signal(NLS)以及nuclear export signal(NES)。為了確認Daxx的NES和NLS motif,將Daxx分為四段:D1、D2、D3和D4,另外將預測為NES和NLS motif的氨基酸進行突變。在顯微鏡下可以觀察到,D1(包含NES motif)以及D4(包含NLS2 motif)可以進入核內,但若是NES或NLS2 motif的突變則會阻斷Daxx的入核,NES及NLS2 motif都與Daxx的nuclear transport有關。不過,若是active SUMO與突變的Daxx或是inactive SUMO與wild type Daxx一起送入細胞內,則可以觀察到無法入核的SUMO或Daxx會被攜帶入核內。因此, SUMO似乎是藉由interaction或sumoylation把突變的Daxx帶入核內,而Daxx似乎也可以藉由interaction將inactive SUMO帶入核內,所以active SUMO及Daxx似乎都會扮演著nuclear transporter的角色。
SUMO is a small ubiquitin-like modifier. The fluorescent fused SUMO (active for sumoylation) localized in the nucleus, while C-terminal truncated SUMO (inactive for sumoylation) diffused in the cytoplasm. Daxx is a SUMO target protein, locates predominantly in the nucleus. It has been identified as a component of the PODs. During extracellular stimulation, Daxx could be recruited to the cytoplasm with the existence of Ask1. Therefore, it is a shuttle protein. Daxx should contain nuclear localization signal (NLS) and nuclear export signal (NES) motifs. To identify the NES and NLS motifs on Daxx, Daxx were truncated into four segments. Several amino acids on the predicted NES and NLS motifs were mutated. Our results showed that the truncated Daxx fragments D1 (containing NES) and D4 (containing NLS2) could be translocated into nucleus independently. However, either NES or NLS2 mutants disrupted their translocation into nucleus. It indicated that both NES and NLS2 motif of Daxx were involved in the nuclear transport. Nevertheless the co-transfection of SUMOs and Daxx showed that the interactions between SUMO active form and Daxx mutants and between inactive SUMO and Daxx wild type rescued the nuclear transport function of Daxx mutants and inactive SUMO. Therefore, SUMO may play a role in the nuclear transport of Daxx by either sumoylation or interaction with Daxx in cytoplasm, and Daxx may recruit inactive SUMOs into nucleus by interaction.
中文摘要……………………………………………………………………I
英文摘要…………………………………………………………………..II
縮寫表……….……………………………………………………………III
壹、 緒論…………………………………………………………………..2
1、 Daxx………………………………………………………………....2
1.1 Daxx的基因構造 (gene structure).................…………................2
1.2 Daxx的蛋白質構造 (protein structure)………………………..2
1.3 Daxx在細胞中的角色 (Cellular function)….…………………4
1.3.1 Daxx與細胞凋亡的關係..…………………………………..4
1.3.1.1 Fas/Ask1 pathway………………………………………....4
1.3.1.2轉形生長因子(TGF)-��..................................................…5
1.3.1.3紫外線(Ultraviolet)照射………………..…………....5
1.3.1.4 Daxx對發育(development)的影響………………………5
1.3.2 Daxx扮演轉錄抑制者的角色…………………………...……6
1.3.2.1 Daxx與轉錄因子的相互作用…………….………..6
1.3.2.1.1 Pax3-FKHR…………………………………………….6
1.3.2.1.2 ETS1…………………………………………………7
1.3.2.1.3 Dek……………………………………………………7
1.3.2.1.4 DMAP1………………………………………………...8
1.3.2.1.5 TSG101………………………………………………...8
1.3.2.1.6 MSP58可調節Daxx的轉錄抑制活性………………....8
1.3.3 Daxx、PML以及HDAC之間的interaction …………….….9
1.3.4 HDAC抑制劑對Daxx的影響……………………………....10
1.3.5 Daxx與CENP-C的相互作用….………………………….10
1.3.6 Daxx為可進出細胞核內外的穿梭蛋白 (shuttle protein)….10
1.3.7 Daxx的轉譯後修飾………………………………………..12
1.3.7.1磷酸化 (Phosphorylation)………………………………..12
1.3.7.2相撲化 (Sumoylation)……………………………….…12
2、 SUMO……………………………………………..……………….13
2.1 SUMO-1…………………………………………………..……..14
2.1.1 SUMO-1的基因構造 (gene structure)……………………14
2.1.2 SUMO-1的蛋白質構造 (protein structure)………………14
2.1.3 SUMO-1以及泛激素(ubiquitin)…………………………..14
2.1.4 SUMO-1在細胞內所扮演的功能…………………………..16
2.1.4.1 DNA修補………………………………………………...16
2.1.4.2細胞週期 (cell cycle)…………………………………….16
2.1.4.3細胞凋亡信號 (Apoptotic signal)……………………….17
2.1.4.4 Ran-GTP脢-活化蛋白(RanGAP1)………………………17
2.1.4.5 NF�羠的抑制物-I�羠���|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|�|18
2.1.4.6 p53………………………………………………………..18
2.1.4.7 DNA拓樸異構脢(topoisomerase)………………….……19
2.1.4.7.1 DNA 拓樸異構脢I (topoisomerase I)……………….19
2.1.4.7.2 DNA拓樸異構脢II (topoisomerase II)…………..…..19
2.1.4.8前骨髓性白血症(promyelocytic leukemia, PML)蛋白….19
2.1.4.9 Sp100……………………………………………………..20
2.2 SUMO-2以及SUMO-3………………………………………….20
2.2.1 SUMO-2和SUMO-3的基因構造 (gene structure)…...……20
2.2.2 SUMO-2和SUMO-3的蛋白質構造 (protein structure)…...21
2.2.3 SUMO-2和SUMO-3在細胞內所扮演的功能……………..21
2.2.3.1 Leucine zipper轉錄因子C/EBP�猁漁a族成員:C/EBP��-1……………………………………………....21
2.2.3.2細胞外壓力對SUMO-2/3的影響………………………..22
2.2.3.3對類澱粉先質蛋白(amyloid precursor protein, APP)代謝途徑的影響………………….…………………………..22
2.3相撲化(sumoylation)………………………..…………………...23
2.3.1相撲化之酵素(sumoylation enzymes)………………..……...25
2.3.2相撲化的一致序列(sumoylation consensus sequence)……...26
2.3.3 SUMO的自我相撲化(self-sumoylation)…………..………..26
3、 實驗室先前的實驗結果…………………………………………..27
3.1酵母菌二次雜交分析(Yeast two-hybrid assay)……………...….27
3.2試管中的相撲化(in vitro sumoylation)………………..………...27
貳、 研究目的…………………………………………………………….29
參、實驗材料及方法……………………………………………………...30
1、 Mammalian expression vectors及氨基酸突變的製備……………30
1.1 pEGFP-C2-Daxx 1、2、3及4的引子…………………………….30
1.2 188IXXLXXLLXL197的氨基酸突變引子………………………..31
1.3 pDsRed1-C1-SUMO-1/2的引子………………………………...31
1.4 pDsRed1-C1/ pEGFP-C2-PML的引子…………………………33
1.5 PCR overlapping extension mutagenesis………………………...33
1.6聚合脢連鎖反應 (PCR)….……………………………………35
1.6.1 PCR所需的機器及藥品……………………………………..35
1.6.2使用AmpliTaq的試劑量…………………………………….35
1.6.3使用pfu polymerase的試劑量……………………………….35
1.6.4產物的長度及PCR conditions……………………………....36
1.6.5 DNA電泳分析……………………………………………….36
2、 DNA cloning……………………………………………………….36
2.1用酵素製造載體及PCR產物的相黏接端……………………...36
2.2切開載體時的試劑量……………………………………………37
2.3切割DNA時的試劑量…………………………………………..37
2.4載體及DNA的黏接……………………………………………..38
2.4.1黏接的試劑量………………………………………………..38
2.5 Competent cells的製備 (TSS method)………..……………….38
2.5.1實驗材料……………………………………………………..38
2.5.2實驗方法……………………………………………………..39
2.6 Competent cells的製備 (CaCl2 method)………………………..39
2.6.1實驗材料……………………………………………………..39
2.6.2實驗方法……………………………………………………..39
2.7 Cloning vectors的transformation……………………………….40
2.8 Cloning vector的篩選 (利用限制酵素)…...…………………...40
2.8.1實驗材料……………………………………………………..40
2.8.2實驗方法…………………………………………………......40
2.9 Cloning vector的確認 (序列辦讀)……………………………...41
2.9.1 Autosequence gel的置備…………………………………….41
2.9.1.1實驗材料………………………………………………….41
2.9.1.2實驗方法………………………………………………….41
2.9.2 DNA sequencing analysis……………………………………42
2.9.2.1實驗材料………………………………………………….42
2.9.2.2 Cycle sequencing ………………………………………...42
2.9.2.2.1 Cycle sequencing的試劑量…………………………..42
2.9.2.2.2 Cycle sequencing的condition………………………...43
2.9.2.3酒精沈澱………………………………………………….43
3、細胞培養……………………………………………………………43
3.1細胞株……………………………………………………………43
3.1.1 HeLa cells……………………………………………………43
3.1.2 Cos-1 cells……………………………………………………44
3.2細胞培養液的成分………………………………………………44
3.3細胞培養液中成分的含量………………………………………45
3.4繼代培養…………………………………………………………45
3.5冷凍保存…………………………………………………………46
3.5.1 Freezing medium的組成分…………………………………..46
3.6解凍………………………………………………………………46
4、 Transfection………………………………………………………..47
4.1實驗方法…………………………………………………………47
4.2 Transfection的試劑量…………………………………………...47
5、 In vivo fluorescence assay ………………………………………..47
5.1實驗材料…………………………………………………………47
5.2實驗方法…………………………………………………………48
6、 SDS-PAGE ………………………………………………………..48
6.1實驗材料…………………………………………………………48
6.2 SDS-PAGE的置備……………………………………………....49
6.2.1 Resolving gel (10%)….………………………………………49
6.2.2 Stacking gel (5%)…………………………………………….50
6.3 SDS-PAGE分析whole cell lysate ……………………………...50
7、 Western blotting…………………………………………………...50
7.1實驗材料…………………………………………………………50
7.2實驗方法…………………………………………………………51
肆、結果…………………………………………………………………...52
1、 螢光蛋白對其融合蛋白的影響………..…………………………52
2、 不活化的SUMOs無法進入到細胞核裡……………..…....……..54
3、 Daxx在細胞中的表現……………...…………………………….56
4、 D1以及D4 入核系統的主導區域……………...…………….....61
4.1 D1的NES motif中leucine的單點突變對Daxx在細胞中位置的影響………………………..……………………………………61
4.2位於D1 NES motif的多重突變(NES*)對Daxx在細胞中位置的影響. ………..……………………………….………………….63
4.3位於D4 NLS2 motif的多重突變(NLS2*)對Daxx在細胞中位置的影響………..…………………..…………..…………………64
4.4 Daxx與綠色螢光蛋白的融合蛋白在細胞內的表現…………..65
5、 活體中(in vivo) SUMO與Daxx的相互影響…………………..…66
5.1相撲化可調節Daxx在細胞中的位置…………………………..66
5.2 SUMO在細胞中的位置受到Daxx的影響…………………..…71
5.3 Daxx的NES以及NLS2 motif會影響Daxx與SUMO-1/2的交互作用 ……………….…………………………………..…….74
6、 相撲化可調節PML片段在細胞中的位置………….……………76
伍、討論…………………………………………………………………...78
1、 相撲化使SUMOs得以進入細胞核…………………….………...78
2、 NES及NLS2區段主宰Daxx進入細胞核………………….…….79
3、 活化的SUMO扮演nuclear transporter的角色………………......82
4、 Daxx扮演nuclear transporter的角色……………………………..83
5、 SUMO與Daxx之間的sumoylation及 interaction………………84
6、 未來的研究方向…………………………………………………..85
陸、參考文獻……………………………………………………………...87
柒、附錄…………………………………………………………………...98
1、載體的map…………………………………………………………98
1.1 pEGFP-C1………………………………………………………..98
1.2 pEGFP-C2………………………………………………………..99
1.3 pDsRed1-C1……………………………………………………100
2、 突變DNA的定序結果…………………………………………..101
2.1 I188A…………………………………………………………...101
2.2 L191A…………………………………………………………..102
2.3 L194A…………………………………………………………..103
2.4 L195A…………………………………………………………..104
2.5 L197A…………………………………………………………..105
2.6 L191、194以及195A (NES*)………………….……………….106
2.7 I188、L191、194以及195A……………………………………..107
2.8 Mono-sumoylation SUMO (SUMO-1*-GG)…………………..108
2.9 Mono-sumoylation SUMO(SUMO-2*-GG)…………………..109
3、 蛋白質的胺基酸序列……………………………………………110
3.1 SUMO-1………………………………………………………..110
3.2 SUMO-2………………………………………………………..110
3.3 Daxx…………………………………………………………….110
3.4 PML…………………………………………………………….111
4、單一相撲化(mono-sumoylation)能力的SUMO-1*/2*過量表現所引起的細胞凋亡…………………………………..………………112
5、 I188、191、194以及195A四個氨基酸同時突變的Daxx在細胞中的位置………………………………………………………..114
6、在D4/SUMO-2-ΔGG的組別中,不活化的SUMO-2 (ΔGG)在核內外的比例……………………………………………………..115
7、比較In vivo fluorescent assay及酵母菌二次雜交分析的結果…..116
8、 Time course of Daxx、D1以及D4……………………………….117
8.1 Daxx…………………………………………………………….117
8.2 D1……………………………………………………………….118
8.3 D4……………………………………………………………….119
8.4 Daxx的nuclear bodies數量……………………………………120
8.5 D1的nuclear bodies數量………………………………………121
8.6 D1的nuclear bodies數量………………………………………122
9、 Immunoprecipitation (免疫沈澱)……………..…………………123
9.1 Cell lysis………………………………………………………..123
9.1.1 NP-40 cell lysis buffer……………………………………...123
9.1.2 Cell lysates的置備………………………………………….122
9.2 Protein A/G beads的置備……………………………………...123
9.2.1 Protein A/G beads的使用比例……………………………..124
9.3 Cell lysates preclearning ……………………………………….124
9.4 Immunoprecipitation (免疫沈澱)………………………………124

表目錄
Table 1比較NLS2 區段中的lysine突變…………………..…………….80
Table 2 Daxx與p53 NES區段序列的比較……….……………………..82

圖目錄
Figure 1 Daxx位在染色體6p21.3…………………………………………1
Figure 2 Daxx有七個exons以及六個introns…………………………….1
Figure 3 SUMO及ubiquitin的氨基酸序列的比對……………………...13
Figure 4 SUMO-1以及ubiquitin的3D structure………………………...15
Figure 5 Sumoylation的步驟……………………………………………..24
Figure 6 SUMO與目標蛋白以isopeptide鍵結………………………….24
Figure 7 PCR overlapping extension mutagenesis………………………..34
Figure 8螢光蛋白的表現………………………………………………...53
Figure 9不活化的SUMOs (-ΔGG)散佈在細胞質中…..………………55
Figure 10預測的NES以及NLS在Daxx上的位置……………………..57
Figure 11細胞中Daxx以及Daxx片段的表現…………………………..58
Figure 12 Daxx形成核小體(nuclear bodies)與其C-端有關………….....59
Figure 13隨著時間的變化,Daxx、D1以及D4在細胞內的位置變化….60
Figure 14 NES motif上的單點突變對Daxx在細胞中位置的影響…….62
Figure 15 NES*多重突變使Daxx散佈在細胞質中……………….……63
Figure 16 NLS*2多重突變使Daxx散佈在細胞質中……………….…...64
Figure 17 Daxx與綠色螢光蛋白的融合蛋白在細胞內的表現………...65
Figure 18 Daxx、D1以及D4會與活化的SUMO-1/2(-GG)存在於核內相同的位置上………………………………………………..67
Figure 19活化的SUMO-1/2(-GG)會攜帶無法入核的NES*突變蛋白進入核內…………………………………………………….….68
Figure 20 活化的SUMO-1/2(-GG)可與NLS2*突變蛋白共同形成核小體……………..…………………………………………………69
Figure 21單一相撲化的SUMO-1*/2* (-K16A及-K11A)突變蛋白可與NES*或NLS2*形成核小體…………………………………….70
Figure 22 Daxx可攜帶不活化SUMOs (-ΔGG)進入核內…………..….72
Figure 23 Daxx的N-端(D1)不能將不活化SUMO-1-ΔGG帶入細胞核內………………………………………………………..……..73
Figure 24 NES*/Daxx及NLS2*/D4與不活化SUMO-1/2-ΔGG無法進入細胞核內…………………………………………………….….75
Figure 25活化的SUMO-1/2 (-GG)可攜帶PML片段的蛋白進入細胞核內………………………………………………………………..77
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