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研究生:李佳瑾
研究生(外文):Chia-Chin Lee
論文名稱:類類泛素變異體的功能分析
論文名稱(外文):Functional study of an ubiquitin-like variant
指導教授:楊文明楊文明引用關係
指導教授(外文):Wen-Ming Yang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:分子生物學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
畢業學年度:96
語文別:中文
論文頁數:85
中文關鍵詞:類泛素急性骨髓白血病後轉譯修飾作用
外文關鍵詞:SUMOPMLpost-translation modifictionHIPK2DAXXsp100
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真核細胞內的後轉譯修飾作用 (post-translational modification) 可調控許多重要的細胞生理活動,包含SUMO (Small Ubiquitin-like Modifier) 蛋白的修飾作用。而SUMOylation主要調控細胞細微的生理功能,例如: PML nuclear body的結構等。近來在本實驗室發現另一個新的SUMO蛋白,稱之為SUMO-13。比對胺基酸序列,可知SUMO-13和SUMO-1有著84%高相似度,且兩者在細胞中的分佈也比其他SUMO family蛋白相似。利用RT-PCR及PCR的方式可證實SUMO-13在human embryonic kidney HEK293細胞中確實存在,且在靈長類動物中保留性高,由於SUMO-13是新發現的蛋白,因此欲找其詳細調控機制。
從confocal microscopy的觀察可知SUMO-13在細胞核中以點狀分佈,利用將其C端的 di-glycine變異成di-alanine,則點狀分佈便消失,代表細胞內SUMO-13多以conjugation form存在。
為了找尋其修飾蛋白,比對SUMO-1已知的修飾蛋白後,推論PML nuclear body (NB)的主要結構蛋白PML可能可被SUMO-13所修飾,利用conjugaiton assay可知PML上的三個SUMO-1 lysine sites可被SUMO-13所修飾,immunofluorescence asasy的結果也意外地發現endogenous PML蛋白可被SUMO-13所增大,相對地SUMO-1卻無此能力。從Western blot分析endogenous PML蛋白表現卻不因SUMO-13而顯著增加,顯示SUMO-13的修飾作用或許是幫助PML NBs蛋白成員的聚集。已知PML NB成員蛋白包括Sp100、HIPK2、DAXX等,利用專一抗體偵測endogenous PML NBs蛋白時,可知SUMO-13幫助endogenous PML NBs的增大。若同時表現SUMO-1時,則endogenous PML增大的效果便被破壞,顯示SUMO-1和SUMO-13可相互競爭。大量表現HIPK2時,可發現許多蛋白會被SUMO-13修飾並和HIPK2發生交互作用。當表現SUMO-13時可幫助HIPK2與PML colocalizaiton,並增加endogenous DAXX spots。
為了了解細胞如何調控SUMO-13,以增大endogenous PML NBs,在p53 deficient H1299細胞株可知SUMO-13仍可增大endogenous PML蛋白,代表SUMO-13調控endogenous PML NBs並非藉由p53 pathway。除此之外,在differentiated HEK293細胞株中,SUMO-13也可修飾重要的stem cell marker—Oct4、Nanog、ZFP42,然而mouse embryonic carcinoma P19中,Oct4卻不會被SUMO-13所修飾,暗示在分化的過程中,SUMO-13的conjugation必須被建立。
本論文結果顯示,SUMO-13可扮演著PML nuclear body增大的調控者,幫助PML nuclear body蛋白聚集,並非透過p53-mediated pathway。此外,SUMO-13 conjugation也可藉由調控Oct4,參與分化過程。
In eukaryotes, post-translational modification by small ubiquitin-like modifiers (SUMO) plays an essential role in some crucial cellular functions, for example, the maintenance of PML nuclear body integrity. Recently, our laboratory discovered an additional SUMO homolog that we called SUMO-13. SUMO-13 is 84% similar to SUMO-1 in peptide sequence. Both of them localize as speckles under the microscope. The expression of SUMO-13 in human embryonic kidney HEK293 cells was characterized by RT-PCR and PCR analysis. However, it remains unclear how SUMO-13 functions in cells.
Confocal microscopy results showed that an unconjugatable mutant of SUMO-13 would abolish the speckle-like localization pattern, suggesting that SUMO-13 predominantly exists as a conjugated form in cells. SUMO-1 localization was mainly nuclear, diffuse and some formed spots.
To find SUMO-13 substrates, we analysed SUMO-1 target proteins first. One of the promising substrates is the scaffold protein of PML nuclear body, PML. Using conjugation assay, three lysine residues of PML were shown to be modified by SUMO-13. Immunofluorescence assay surprisingly revealed that SUMO-13, not SUMO-1, could enlarge endogenous PML protein. Without increasing in endogenous PML expression, we hypothesized that SUMO-13 has the ability to recruit PML nuclear body proteins. In agreement with out hypothesis, endogenous PML nuclear body proteins, such as Sp100 and HIPK2, were also enlarged by SUMO-13 and were disrupted with co-expressing SUMO-1. It indicates that SUMO-1 competes with SUMO-13. HIPK2 was conjugated by SUMO-13 as well. Conjugation assay also provided evidence that numerous SUMO-13 conjugated proteins associate with HIPK2. In addition, SUMO-13 promoted co-localization of HIPK2 and PML and increased endogenous DAXX spots.
To characterize how SUMO-13 is regulated to enlarge PML nuclear bodies, we treated cells in response to different stresses. In p53-deficient H1299 cells, PML nuclear bodies still increased dramatically in size by SUMO-13, demonstrating that p53 is dispensable for SUMO-13-mediated PML nuclear body regulation. In differentiated HEK293 cells, Oct4, Nanog, and ZFP42, three important stem cell markers were modified by SUMO-13. However, Oct4 could not be modified by SUMO-13 in mouse embryonic carcinoma P19 cells, suggesting SUMO-13-conjugation of Oct4 is necessery during differentiation.
Taken together, our data demonstrate that SUMO-13 is a modulator of PML nuclear bodies, recruiting other PML nuclear body proteins in a p53-independent pathway. SUMO-13 might also establish a conjugation pattern of Oct4 during differentiation.
中文摘要……………………………………………………………………………………. 1
英文摘要……………………………………………………………………………………. 2
緒論…………………………………………………………………………………………. 3
一、前言………………………………………………………………………………… 3
二、SUMO背景介紹…………………………………………………………………… 3
(一)SUMO的歷史與概觀………………………………………………………. 3
(二)SUMO family……………………………………………………………….. 3
(三)SUMOylation consensus motif……………………………………………... 4
(四)SUMO conjugation machinery……………………………………………... 4
(五)SUMOylation功能………………………………………………………...... 5
1. Protein targeting……………………………………………….................. 6
2. Transcription……………………………………………………………... 6
3. DNA repair……………………………………………………………….. 7
(六)SUMO interaction machinery………………………………………………. 7
(七)SUMO binding的功能 ……………………………………………………... 8
(八)SUMO在核外的功能………………………………………………………. 8
1. Mitochondria……………………………………………………………... 9
2. Endoplasmic Reticulum (ER)…………………………………………….. 9
3. Plasma membrane………………………………………………………... 9
4. G-protein signalling………………………………………………………. 10
(九)神經系統的調控機能及疾病………………………………………………. 11
三、 PML nuclear body…………………………………………………………………. 11
(一)PML nuclear body (NB) 的簡介…………………………………………… 11
(二)調控PML NBs的表現……………………………………………………… 12
(三)PML的SUMOylation……………………………………………………….. 12
(四)PML NB成型理論………………………………………………………….. 13
(五)PML NBs的動態結構……………………………………………………… 13
(六)PML NBs的組成蛋白……………………………………………………… 14
1. PML……………………………………………………………………… 14
2. Sp100……………………………………………………………………... 15
3. HIPK2……………………………………………………………………. 15
4. DAXX……………………………………………………………………. 16
四、研究目的…………………………………………………………………………… 17
五、研究策略…………………………………………………………………………… 17
材料與方法………………………………………………………………………………… 19
一、質體 DNA的構築(Plasmid construction)及 干擾性核醣核酸(RNAi)…… 19
二、細胞株(Cell lines)和基因轉移感染(Transfection)………………………… 21
三、免疫沈澱法(Immunoprecipitation) 及西方免疫墨點法(Western blot)…… 21
四、純化蛋白複合體(Immunoaffinity)…………………………………………….. 22
五、螢光顯微鏡 (Fluorescence microscopy)……………………………………….. 23
六、免疫螢光染色法(Immunofluorescence)及雷射掃描共軛焦顯微鏡
(Confocal microscopy)………………………………………………………….. 23
七、轉錄活性之檢測 (Dual-Luciferase Reporter Assay)……………………………… 24
結果…………………………………………………………………………………………. 25
一、 SUMO-13可在人類細胞內表現,在哺乳類動物中保留性高………………….. 25
二、 SUMO-13在細胞中以點狀分佈,多以conjugation form存在………………….. 25
三、PML nuclear bodies (NBs)蛋白PML的三個SUMO-1 conjugation sites可被
SUMO-13修飾,而p53並非SUMO-13的目標蛋白……………………………….
26
四、具有修飾能力的SUMO-13可令endogenous PML NBs增大,並可與PML蛋白
發生蛋白質交互作用………………………………………………………………
27
五、SUMO-13和SUMO-1之間存在著競爭的關係,SUMO-1可破壞SUMO-13幫助
內生性PML增大的現象…………………………………………………………… 28
六、PML NBs的HIPK2也會被SUMO-13修飾,其修飾位置並非SUMO-1
conjugation site,並且SUMO-13可增加endogenous HIPK2 domains的數量…… 29
七、SUMO-13也幫助PML NBs成員蛋白聚集至細胞核內,增大其大小及數量….. 30
八、SAE1、Ubc9可作為SUMO-13的E1、E2,Ubc9 (DN) 會破壞SUMO-13幫助
endogenous HIPK2 domains的大小和數量……………………………………….. 30
九、Aresenic Trioxide可調控 PML-containing NBs的大小,H1299細胞中證實
SUMO-13並非藉由調控p53,以增大內生性PML蛋白 ………………………… 31
十、SUMO-13具有非常強的抑制轉錄活性,但並不參與p53-dependent
transcription activity………………………………………………………………... 32
十一、Stem cell transcription factors—human Rex-1、Oct4、Nanog皆可被SUMO-
13所修飾…………………………………………………………………………
32
討論………………………………………………………………………………………… 34
一、SUMOylation與dynamic nuclear architecture…………………………………….. 34
二、SUMO-13 protein complex分析…………………………………………………… 36
三、PML、HIPK2的SUMOylation和interaction……………………………………… 36
參考文獻…………………………………………………………………………………… 38
圖表…………………………………………………………………………………………. 49
附圖………………………………………………………………………………………… 71
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