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題名 Hes-1 的類小泛素化修飾可調節 Hes-1 蛋白質的穩定及 GluR1 的表現
Sumoylation of Hes-1 regulates the protein stability of Hes-1 and GluR1 expression
作者 許芳芸
Hsu, Fang Yun
貢獻者 李小媛<br>趙知章
Lee, Hsiao Yuen<br>Chao, Chih Chang
許芳芸
Hsu, Fang Yun
關鍵詞 穩定度
類小泛素化修飾
stability
sumoylation
日期 2011
上傳時間 30-Oct-2012 11:46:17 (UTC+8)
摘要 轉譯後修飾作用
(post-translational modifications) 包含甲基化
(methylation)、磷酸化
(phosphorylation)、泛素化
(ubiquitination)、類小泛素
化修飾
(sumoylation) 等。過去有研究指出類小泛素化修飾可以調節目標蛋白
質的穩定度，進而調節許多細胞內反應，例如：細胞核運輸作用、
DNA 複
製、調節轉錄作用、染色體分離、訊息傳遞、細胞週期調控、DNA 修補作用等
現象。類小泛素化修飾是藉由一系列的酵素，使類小泛素這個蛋白質能夠修飾
目標蛋白質的
lysine
殘基。
類小泛素化修飾是一個可逆性動態修飾過程，類
小泛素化修飾連結途徑包含有三個主要的步驟：
活化 (activation)，結合
(conjugation)，連接 (ligation)，它們分別是藉由
E1、E2 和
E3 這三種不同的
酵素催化的。本篇研究主要是藉由類小泛素
E3 連接酶 PIAS1 進行修飾作用，
我們發現
Hairy and Enhancer of split 1 (Hes-1) 蛋白質可被類小泛素修飾。若
將類小泛素
E3 連接酶 PIAS1 突變，就無法讓野生型
Hes-1 進行類小泛素修
飾化，證實
PIAS1 的參與對於類小泛素化修飾扮演重要的角色。除此之外，
將類小泛素目標蛋白質
Hes-1 序列上第八個位置的
lysine 突變，會抑制
Hes-1 進行類小泛素化修飾。因此，透過
PIAS1 所進行的類小泛素化修飾可以
使目標蛋白質
Hes-1 蛋白質更為穩定。之後更進一步探討在空間學習與記憶
中，Hes-1 進行類小泛素化修飾與
GluR1 蛋白質表現的關係。實驗結果顯示，
Hes-1 進行類小泛素化修飾使空間學習與記憶變差並使
GluR1 蛋白質表現下
降。
There are several post-translational modifications including methylation、
phosphorylation、ubiquitination、sumoylation, etc. Previously studies
indicated that sumoylation can regulate target protein stability. Sumoylation
also modulates many cellular processes, including nuclear transport, DNA
replication, transcription, chromosome segregation, signal transduction, cell
cycle and DNA repair. Sumoylation is a process mediated by SUMOs which
are attached to specific lysine residues of target proteins by the action of a
series of enzymes. Sumoylation is a dynamically reversible process.
Sumoylation consists of three steps：activation, conjugation and ligation,
which are respectively mediated by E1, E2 and E3 ligase. This study focuses
on SUMO modification by E3 ligase. Here, we identified a new target protein,
Hairy and Enhancer of split 1 (Hes-1), for SUMO conjugation. The E3 ligase
deficient mutant of PIAS1 that leads to failure of Hes-1 protein sumoylation.
We demonstrared that PIAS1 is involved in SUMO modification of Hes-1. In
addition mutantion of Hes-1 protein on lysine 8 residue that inhibits the
sumoylation of Hes-1. Therefore, sumoylation of Hes-1 regulates the protein
stability of Hes-1. Further study of the relationship between sumoylation of
Hes-1 and GluR1 in spatial memory formation indicated that spatial memory
is impaired and GluR1 protein expression is decreased upon sumoylation of
Hes-1.
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描述 碩士
國立政治大學
神經科學研究所
99754005
100
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0099754005
資料類型 thesis
dc.contributor.advisor 李小媛<br>趙知章zh_TW
dc.contributor.advisor Lee, Hsiao Yuen<br>Chao, Chih Changen_US
dc.contributor.author (Authors) 許芳芸zh_TW
dc.contributor.author (Authors) Hsu, Fang Yunen_US
dc.creator (作者) 許芳芸zh_TW
dc.creator (作者) Hsu, Fang Yunen_US
dc.date (日期) 2011en_US
dc.date.accessioned 30-Oct-2012 11:46:17 (UTC+8)-
dc.date.available 30-Oct-2012 11:46:17 (UTC+8)-
dc.date.issued (上傳時間) 30-Oct-2012 11:46:17 (UTC+8)-
dc.identifier (Other Identifiers) G0099754005en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/54796-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 99754005zh_TW
dc.description (描述) 100zh_TW
dc.description.abstract (摘要) 轉譯後修飾作用
(post-translational modifications) 包含甲基化
(methylation)、磷酸化
(phosphorylation)、泛素化
(ubiquitination)、類小泛素
化修飾
(sumoylation) 等。過去有研究指出類小泛素化修飾可以調節目標蛋白
質的穩定度，進而調節許多細胞內反應，例如：細胞核運輸作用、
DNA 複
製、調節轉錄作用、染色體分離、訊息傳遞、細胞週期調控、DNA 修補作用等
現象。類小泛素化修飾是藉由一系列的酵素，使類小泛素這個蛋白質能夠修飾
目標蛋白質的
lysine
殘基。
類小泛素化修飾是一個可逆性動態修飾過程，類
小泛素化修飾連結途徑包含有三個主要的步驟：
活化 (activation)，結合
(conjugation)，連接 (ligation)，它們分別是藉由
E1、E2 和
E3 這三種不同的
酵素催化的。本篇研究主要是藉由類小泛素
E3 連接酶 PIAS1 進行修飾作用，
我們發現
Hairy and Enhancer of split 1 (Hes-1) 蛋白質可被類小泛素修飾。若
將類小泛素
E3 連接酶 PIAS1 突變，就無法讓野生型
Hes-1 進行類小泛素修
飾化，證實
PIAS1 的參與對於類小泛素化修飾扮演重要的角色。除此之外，
將類小泛素目標蛋白質
Hes-1 序列上第八個位置的
lysine 突變，會抑制
Hes-1 進行類小泛素化修飾。因此，透過
PIAS1 所進行的類小泛素化修飾可以
使目標蛋白質
Hes-1 蛋白質更為穩定。之後更進一步探討在空間學習與記憶
中，Hes-1 進行類小泛素化修飾與
GluR1 蛋白質表現的關係。實驗結果顯示，
Hes-1 進行類小泛素化修飾使空間學習與記憶變差並使
GluR1 蛋白質表現下
降。		zh_TW
dc.description.abstract (摘要) There are several post-translational modifications including methylation、
phosphorylation、ubiquitination、sumoylation, etc. Previously studies
indicated that sumoylation can regulate target protein stability. Sumoylation
also modulates many cellular processes, including nuclear transport, DNA
replication, transcription, chromosome segregation, signal transduction, cell
cycle and DNA repair. Sumoylation is a process mediated by SUMOs which
are attached to specific lysine residues of target proteins by the action of a
series of enzymes. Sumoylation is a dynamically reversible process.
Sumoylation consists of three steps：activation, conjugation and ligation,
which are respectively mediated by E1, E2 and E3 ligase. This study focuses
on SUMO modification by E3 ligase. Here, we identified a new target protein,
Hairy and Enhancer of split 1 (Hes-1), for SUMO conjugation. The E3 ligase
deficient mutant of PIAS1 that leads to failure of Hes-1 protein sumoylation.
We demonstrared that PIAS1 is involved in SUMO modification of Hes-1. In
addition mutantion of Hes-1 protein on lysine 8 residue that inhibits the
sumoylation of Hes-1. Therefore, sumoylation of Hes-1 regulates the protein
stability of Hes-1. Further study of the relationship between sumoylation of
Hes-1 and GluR1 in spatial memory formation indicated that spatial memory
is impaired and GluR1 protein expression is decreased upon sumoylation of
Hes-1.		en_US
dc.description.tableofcontents 誌
謝
..................................................................................................................................................Ⅰ
中文摘要............................................................................................................................................Ⅱ
英文摘要............................................................................................................................................Ⅲ
目
錄
..................................................................................................................................................Ⅳ
圖
次
..................................................................................................................................................Ⅶ
英文縮寫表.......................................................................................................................................Ⅷ
第一章、緒論
...................................................................................................................................1
第一節、學習與記憶...................................................................................................................2
一、學習與記憶的定義.........................................................................................................2
二、學習與記憶的種類.........................................................................................................2
三、參與學習與記憶的腦區...............................................................................................3
第二節、空間學習記憶與海馬迴組織................................................................................4
ㄧ、海馬迴的構造與投射路徑..........................................................................................4
二、海馬迴相關的動物行為模式.....................................................................................5
第三節、Hes-1蛋白質介紹.....................................................................................................6
一、Hes-1基因結構與轉錄活性.......................................................................................6
二、Hes-1基因表現的訊號調控......................................................................................7
三、Hes-1基因在神經發育系統的表現........................................................................8
第四節、類小泛素化修飾........................................................................................................9
一、類小泛素結構與分類...................................................................................................9
二、類小泛素可逆性修飾途徑.......................................................................................10
三、類小泛素化修飾的功能............................................................................................12
第五節、類小泛素E3連接酶PIAS1蛋白質介紹..........................................................14
一、PIAS家族介紹..............................................................................................................14
二、PIAS結構介紹與類小泛素化修飾的關係.........................................................14
第六節、
本論文之研究目的及策略.................................................................................16
第二章、實驗材料與方法...........................................................................................................17
第一節、細胞培養
(Cell culture)........................................................................................18
一、細胞解凍...........................................................................................................................18
二、細胞培養...........................................................................................................................18
三、冷凍細胞...........................................................................................................................18
第二節、細胞轉染
(Transfection).......................................................................................19
一、細胞轉染...........................................................................................................................19
二、蛋白質均質液的萃取...................................................................................................19
第三節、西方墨點法
(Western blot).................................................................................19
一、蛋白質濃度測定及樣本配製....................................................................................19
二、硫酸十二酯鈉聚丙醯胺凝膠製備...........................................................................20
三、膠體電泳...........................................................................................................................21
四、蛋白質電泳轉漬法.......................................................................................................21
五、免疫染色法......................................................................................................................21
第四節、共同免疫沈澱法 (Co-immunoprecipitation, Co-IP)..................................22
第五節、構建質體
(Plasmid construction).....................................................................22
一、聚合酶連鎖反應及構建質體....................................................................................22
二、轉型...................................................................................................................................22
三、小量質體
DNA
的抽取...............................................................................................23
四、
建構定點突變之質體.................................................................................................24
五、菌液的保存......................................................................................................................24
第六節、蛋白質穩定分析 (Protein stability assay)....................................................24
第七節、實驗動物
(Experimental animals)...................................................................24
第八節、海馬迴內基因轉染作用 (transfection)............................................................25
一、立體定位手術與埋管..................................................................................................25
二、質體基因與聚乙烯亞胺混合物的製備.................................................................25
三、海馬迴
CA1 區域注射................................................................................................25
第九節、動物行為實驗：莫氏水迷津實驗
(Morris water maze).........................26
一、水迷津試驗器材............................................................................................................26
二、隱藏式平台水迷學習津試驗....................................................................................26
三、分離腦組織......................................................................................................................27
四、腦組織蛋白質萃取.......................................................................................................27
五、海馬迴組織之免疫沈澱與西方墨點法.................................................................27
第十節、藥物的製備
(Preparation of drugs).................................................................27
第十ㄧ節、統計分析 (Statistics).........................................................................................28
第三章、實驗結果
.......................................................................................................................29
第一節、 Hes-1 透過
PIAS1 進行類小泛素化修飾....................................................30
第二節、探討類小泛素化修飾
Hes-1 的
lysine 位置................................................33
第三節、類小泛素修飾化影響
Hes-1 蛋白質穩定度.................................................37
第四節、類小泛素修飾化影響內生性
Hes-1 蛋白質的穩定度
............................42
第五節、Hes-1 透過
PIAS1 進行類小泛素化修飾影響
Hes-1 蛋白質穩定度
........................................................................................................................................49
第六節、Hes-1 進行類小泛素化修飾調節空間學習記憶及海馬迴
CA1 區域
GluR1 蛋白質的表現...............................................................................................57
第四章、討論
................................................................................................................................60
第五章、結論
................................................................................................................................70
參考文獻...........................................................................................................................................72
附錄.....................................................................................................................................................82
附錄一、Hes-1基因的
conserved domains....................................................................82
附錄二、類小泛素化修飾連結途徑.......................................................................................83
附錄三、PIAS1 結構....................................................................................................................84
附錄四、Hes-1 蛋白質穩定度.................................................................................................85		zh_TW
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0099754005en_US
dc.subject (關鍵詞) 穩定度zh_TW
dc.subject (關鍵詞) 類小泛素化修飾zh_TW
dc.subject (關鍵詞) stabilityen_US
dc.subject (關鍵詞) sumoylationen_US
dc.title (題名) Hes-1 的類小泛素化修飾可調節 Hes-1 蛋白質的穩定及 GluR1 的表現zh_TW
dc.title (題名) Sumoylation of Hes-1 regulates the protein stability of Hes-1 and GluR1 expressionen_US
dc.type (資料類型) thesisen
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