FoxO6在肌原母細胞中的代謝及分化中所扮演的角色

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研究生：	黃暐捷 Wei Chieh Huang
論文名稱：	FoxO6在肌原母細胞中的代謝及分化中所扮演的角色 The roles of FoxO6 in myoblast metabolism and differentiaion
指導教授：	陳盛良 Shen Liang Chen
口試委員:
學位類別：	碩士 Master
系所名稱：	生醫理工學院 - 生命科學系 Department of Life Science
畢業學年度：	96
語文別：	中文
論文頁數：	102
中文關鍵詞：	FoxO轉錄因子
外文關鍵詞：	FoxO transcription factor
相關次數：	點閱：26 下載：0
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FoxO轉錄因子已經被指出在細胞中有多樣的功能，包括葡萄糖的代謝、壓力反應、分化、細胞週期、細胞的死亡與生存。在FoxO家族成員中的foxo6主要表達在正在發育階段的腦部及肌肉組織，但是其在骨骼肌中主要的功能目前還不知道。PGC-1α是一個轉錄作用的協同活化子且也是一個重要的代謝調控者。而PGC-1α也會調控粒線體的生成，所以當在骨格肌大量表達PGC-1α會導致粒腺體含量增加。當我們誘導C2C12-mFoxO6肌原母細胞株去經歷終極分化，其肌管的大小及肌管的數量都遠比C2C12-control肌原母細胞株來得小及少。當我們誘導Sol8-mFoxO6肌原母細胞株分化，也可以觀察到並沒有肌管的形成。然而我們觀察到C2C12-mFoxO6細胞週期主要都在G0/G1期。我們開始去分析adheren junction的表現量，在細胞分化階段中，這些adheren junction的基因表現量在C2C12穩定表現FoxOs的細胞株中並沒有太大的不一樣，但是在Sol8-mFoxO6細胞株中它們表現量幾乎都是被調控下降的，我們進一步發現Sol8-mFoxO6及C2C12-mFoxO6的分化情形可以在處理胰島素之後有所回復且在Sol8-mFoxO6中其MyoD、myogenin及M-cadherin的表現量可以被回復增加。我們也發現在緊靠擠滿的C2C12中大量表現FoxO6可以抑制PGC-1α的表現，因此我們認為也許是FoxO6經由結合到PGC-1α啟動子上面導致其活性被抑制。經由Reporter assay證明FoxO6的確可以抑制PGC-1α啟動子的活性。在未來，我們希望可以明確知道PGC-1α與FoxO6之間調控的路徑及其對於肌肉分化調控的路徑為何。

FoxO transcription factors have been implicated in regulating diverse cellular functions including glucose metabolism, stress response, differentiation, cell cycle, cell death and cell survival. One of the members, Foxo6, is majorly expressed in the developing brain and muscle but whose functions in skeletal muscle are largely unknown. PGC-1α is a transcriptional coactivator and important metabolic regulator. It regulates mitochondrial biogenesis and overexpression of PGC-1α results in mitochondrial content increase in skeletal muscle. When C2C12-mFoxO6 myoblast were induced to undergo terminal differentiation, the number and size of myotube formed were significantly smaller than that of C2C12-control cells. No myotube formation was observed when Sol8-mFoxO6 myoblasts were induced to differentiation. However strong cell cycle exit was observed in C2C12-mFoxO6 cells. We set out to analyze the expression of adheren junction. At differentiation stage, the expression levels of these genes are not significantly different among C2C12 stable clones. But they genes were down-regulated in Sol8-mFoxO6. We further found that terminal differentiation of Sol8-mFoxO6 and C2C12-mFoxO6 can be rescued by insulin treatment and expression of myoD, myogenin and M-cadherin can be increased in Sol8-mFoxO6 cells. We also found that overexpression of Foxo6 repress expression of PGC-1α gene in confluent C2C12 myoblast. Thus, we think Foxo6 protein may inhibit PGC-1α promoter activity via direct binding to it. Reporter assays demonstrate that FoxO6 suppresses the PGC-1 promoter activity. In the future, we hope that we can define the regulation network involing PGC-1 and FoxO6 and how myogenesis is regulated by the network.

目錄
中文摘要………………………………………………………………………………i
英文摘要…………………………………………………………………………… ii
誌謝………………………………………………………………………………… iii
目錄……………………………………………………………………………………I
圖目錄……………………………………………………………………………… V
縮寫與全名對照表…………………………………………………………………VII
藥品及材料…………………………………………………………………………VII
第一章、序論…………………………………………………………………………1
1. 肌肉的起源……………………………………………………………………… 1
2. MRF、MEF家族與肌肉細胞生長及分化的關係………………………………2
3. FoxO轉錄因子…………………………………………………………………… 4
4. PGC-1 ( peroxisome proliferative activated receptor, gamma, coactivator 1 ) family ……………………………………………………………………………… 10
5. 研究動機與目的…………………………………………………………………13
第二章、實驗方法與材料……………………………………………………………15
2.1 實驗材料……………………………………………………………………… 15
2.1.1 細胞株…………………………………………………………… 15
2.1.2 細胞培養………………………………………………………… 15
2.1.3 菌株 ………………………………………………………………15
2.1.4 菌株培養 …………………………………………………………15
2.1.5 菌株的保存 ………………………………………………………15
2.2 質體建構……………………………………………………………………… 16
2.2.1 質體建構之基本流程…………………………………………… 16
2.2.2 載體DNA (pGL3 basic) 的製備……………………………… 20
2.2.3 pMSCV-neo-FOXOs 表現載體之構築…………………………20
2.2.4 mPGC-1α promoter 5，端缺失……………………………………21
2.3 穩定細胞株的製備…………………………………………………………… 22
2.3.1  細胞培養…………………………………………………………22
2.3.2  轉染作用 (Transfaction) …………………………………… 22
2.3.3  篩選穩定細胞株…………………………………………………23
2.3.4  建立在 C2C12 及Sol8 所表現的穩定細胞株………………… 23
2.4 RT-PCR…………………………………………………………………………23
2.4.1  Total RNA 的抽取 …………………………………………… 23
2.4.2  反轉錄酶反應 (Reverse Transcriptase, RT) ……………… 23
2.4.3  聚合酶鏈反應 ( Polymerase Chain Reaction, PCR )………24
2.4.4  PCR反應在肌肉特異性基因中的各個條件…………………… 24
2.5 西方墨點實驗 (Western blot) ……………………………………………… 25
2.5.1  總蛋白質的製備…………………………………………………25
2.5.2  SDS-polyacryamide Gel Electropheresis………………………26
2.5.3  轉印 (Transfer) ……………………………………………… 26
2.5.4  Blocking 以及 Antibody  辨識……………………………… 26
2.5.5  抗體脫附 (Striping) ………………………………………… 27
2.6 在不分化的穩定細胞株中處理藥劑的實驗 (insulin、Y27632及A23187 )
……………………………………………………………………………………… 27
2.6.1  細胞培養…………………………………………………………27
2.6.2  藥劑處理…………………………………………………………28
2.6.3  DAPI染色……………………………………………………… 28
2.6.4  將細胞株中的細胞核量化………………………………………28
2.6.5  RT-PCR………………………………………………………… 28
2.7 流式細胞儀分析……………………………………………………………… 28
2.7.1  細胞培養…………………………………………………………28
2.7.2  細胞前置處理……………………………………………………29
2.7.3  流式細胞儀數據分析……………………………………………29
2.8 小鼠肌肉組織RNA的抽取……………………………………………………29
2.9   Imunohistochemistry……………………………………………………… 30
第三章、結果…………………………………………………………………………31
3.1、在肌纖維母細胞 (C2C12、Sol8) 中穩定表達FoxO6會影響細胞在分化型態上的改變…………………………………………………………………………… 31
3.2、Catenin與Cadherin及與肌肉細胞分化相關基因於FoxOs穩定表達細胞株中之表現情形……………………………………………………………………… 31
3.2.1 大量表現FoxOs對C2C12的影響………………………………  33
3.2.2 大量表現FoxOs對Sol8的影響 …………………………………33
3.3、在處理insulin、Y27632下其對Sol8-mFoxO6不分化的細胞株所造成的影響及觀察肌肉細胞分化的特異性相關基因表現的變化………………………… 34
3.4、在C2C12細胞株中大量表達FoxOs對於細胞週期的影響……………………35
3.4.1 大量表現FoxOs的PMB時期對於細胞週期的影響…………… 35
3.4.2 大量表現FoxOs的CMB時期對於細胞週期的影響…………… 36
3.5、在纖維肌母細胞株中探討肌肉分化特異性基因對mFoxO6 promter的影響
……………………………………………………………………………………… 37
3.6、大量表達FoxOs細胞株中對於PGC-1家族基因表現的影響………………37
3.6.1 大量表達FoxOs的C2C12細胞株對於PGC-1家族基因表現的影響…………………………………………………………………………………… 38
3.6.2 大量表達FoxOs的Sol8細胞株對於PGC-1家族基因表現的影響
……………………………………………………………………………………… 38
3.7、FoxOs轉錄因子在老鼠纖維母細胞 (C3H10T1/2) 對於PGC-1α promoter的影響……………………………………………………………………………… 39
3.8、FoxOs轉錄因子在老鼠纖維肌母細胞 (C2C12) 對於PGC-1α promoter的影響…………………………………………………………………………………… 40
3.9、在老鼠纖維肌母細胞中隨著FoxO6的濃度增加對於PGC-1α promoter (-3229~ +22)的影響……………………………………………………………… 40
3.10、FoxO6轉錄因子對於各段PGC-1α promoter活性的影響……………… 40
3.11、隨著ICR小鼠年紀的增長藉此來觀察foxos在其後腿肌肉組織表現量的變化…………………………………………………………………………………… 41
第四章、討論…………………………………………………………………………43
4.1、在肌纖維母細胞 (C2C12、Sol8) 中穩定表達FoxO6會影響細胞分化型態及肌肉終極分化過程中特異基因的表現量……………………………………… 43
4.2、Insulin及Y-27632對於Sol8-FoxO6細胞株分化上的影響……………… 44
4.3、大量表達FoxOs的C2C12細胞株對於細胞週期的影響……………………46
4.4、在纖維肌母細胞株中探討肌肉分化特異性基因對mFoxO6 promter的影響…………………………………………………………………………………… 47
4.5、FoxOs轉錄因子對於PGC-1α promoter的調控影響………………………47
4.6、隨著ICR小鼠年紀的增長foxos在其後腿肌肉組織表現量的變化………49
4.7、未來將進行的實驗……………………………………………………………49
第五章、參考文獻……………………………………………………………………78
附錄一……………………………………………………………………………… 82
I. 溶液及試劑配方…………………………………………………………………82
II. 藥品試劑……………………………………………………………………… 85
III. 酵素和限制酶…………………………………………………………………85
IV. 抗體…………………………………………………………………………… 85
附錄二……………………………………………………………………………… 86
I. Primer 對照表………………………………………………………………… 86
II. 與肌肉分化相關基因的primer對照表………………………………………89
III. Plasmid 對照表………………………………………………………………90
<表一>……………………………………………………………………………… 92
<表二>……………………………………………………………………………… 93
<表三>……………………………………………………………………………… 94
<表四>……………………………………………………………………………… 95
<表五>……………………………………………………………………………… 96
<表六>……………………………………………………………………………… 97
<表七>……………………………………………………………………………… 98
<表八>……………………………………………………………………………… 99
<表九>………………………………………………………………………………100
<表十>………………………………………………………………………………101
<表十一>……………………………………………………………………………102
圖目錄
圖一、大量表達FoxO6、FoxO6-T26A及FoxO6-S184A在C2C12細胞株中的形態圖………………………………………………………………………………… 50
圖二、大量表達FoxO6在Sol8細胞株中的形態圖………………………………51
圖三、在大量表達FoxOs的C2C12細胞株中其CMB時期對於肌肉分化的特異基因mRNA表現量的影響…………………………………………………………… 52
圖四、在大量表達FoxOs的C2C12細胞株中其MT時期對於肌肉分化的特異基因mRNA表現量的影響……………………………………………………………… 53
圖五、在大量表達FoxOs的Sol8細胞株中其CMB時期對於肌肉分化的特異基因mRNA表現量的影響 …………………………………………………………… 54
圖六、在大量表達FoxOs的Sol8細胞株中其MT時期對於肌肉分化的特異基因mRNA表現量的影響 ……………………………………………………………… 55
圖七、在Sol8-FoxO6-wt細胞株中處理胰島素及Y27632來觀察其對細胞分化形態的影響及肌肉特異基因mRNA的表現量 …………………………………… 58
圖八、在大量表達FoxOs的C2C12細胞株PMB時期利用流式細胞儀來觀察FoxOs對細胞週期的調控影響…………………………………………………………… 59
圖九、在大量表達FoxOs的C2C12細胞株CMB時期利用流式細胞儀來觀察FoxOs對細胞週期的調控影響…………………………………………………… 60
圖十、T-vector-FoxO6 啟動子質體建構………………………………………… 61
圖十一、pGL3 basic-FoxO6啟動子質體建構…………………………………… 62
圖十二、肌肉特異性的轉錄因子對於mFoxO6 啟動子活性的影響…………………………………………………………………………………… 63
圖十三、在大量表達FoxOs的C2C12細胞株中其CMB時期對於PGC-1家族mRNA表現量的影響……………………………………………………………… 64
圖十四、在大量表達FoxOs的C2C12細胞株中其MT時期對於PGC-1家族mRNA表現量的影響……………………………………………………………………… 65
圖十五、在大量表達FoxOs的Sol8細胞株中其CMB時期對於PGC-1家族mRNA表現量的影響……………………………………………………………………… 66
圖十六、在大量表達FoxOs的Sol8細胞株中其MT時期對於PGC-1家族mRNA表現量的影響……………………………………………………………………… 67
圖十七、pGL3 basic-pGC-1α啟動子質體建構 …………………………………68
圖十八、老鼠纖維母細胞在含有生長因子的培養基下其Forkhead轉錄因子對於mPGC-1α啟動子活性的影響 ……………………………………………………69
圖十九、老鼠纖維母細胞在分化培養基下其Forkhead轉錄因子對於mPGC-1α啟動子活性的影響…………………………………………………………………70
圖二十、在C2C12中培養在5% Hose Serum下其Forkhead轉錄因子對於mPGC-1α啟動子轉錄活性的影響……………………………………………… 71
圖二十一、在C2C12中培養在20% Foetal Bovine Serum下其Forkhead轉錄因子對於mPGC-1α啟動子轉錄活性的影響……………………………………… 72
圖二十二、在C2C12中培養在20% Foetal Bovine Serum下當逐量增加FoxO6轉錄因子時會抑制mPGC-1α啟動子的轉錄活性………………………………… 73
圖二十三、FoxO6轉錄因子對於各段mPGC-1α啟動子活性的影響……………74
圖二十四、FoxO6轉錄因子抑制mPGC-1α啟動子 -2310 ~ -768活性 ……… 75
圖二十五、FoxO6轉錄因子抑制mPGC-1α啟動子 -2310 ~ --1902及-1312 ~ -768活性………………………………………………………………………………… 76
圖二十六、foxos於ICR小鼠後腿肌肉組織中隨著年齡的增長其mRNA level的變化………………………………………………………………………………… 77

                                

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