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研究生:林信志
研究生(外文):Shin-Chih Lin
論文名稱:分析不同的PP2AB調節次單元在功能上的差別
論文名稱(外文):Functional comparison of distinct PP2A B regulatory subunits
指導教授:蔣輯武蘇五洲蘇五洲引用關係
指導教授(外文):Chi-Wu ChiangWu-Chou Su
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:71
中文關鍵詞:磷酸化細胞週期
外文關鍵詞:PP2A holoenzymeB55αB56γ3p27contact inhibition
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PP2A是細胞中一種主要的Ser/Thr蛋白磷酸酶,參與在許多細胞活動中。PP2A完全酶包含了三個次單元體,36kDa的催化次單元(PP2A/C),65kDa的結構次單元(PP2A/A),跟具有相當多樣性的調節次單元(PP2A/B)。調節次單元被認為是具有決定PP2A受質特異性(substrate specificity)以及次細胞定位(subcellular localization)的功能,而目前已知調節次單元至少有四個家族,分別為B, B’, B’’, B’’’。我們實驗室先前已經發現PP2A AB55αC完全酶會跟Akt有交互作用並且會選擇性去磷酸化Akt的磷酸位點Thr308而非Ser473,而Akt是在細胞中具有重要的調控作用。我們在此論文中主要的研究是,要分析兩個不同家族的調節次單元體B55α和 B56γ3, 在不同的細胞株之中,對於一些細胞功能包括AKT的活化、細胞生長和細胞週期有何影響。跟先前研究相符合的是,在NIH3T3和3T3-L1的細胞株之中,過度表現B55α而非B56γ3會降低血清刺激的Akt在位點Thr308的磷酸化程度。在人類的肺癌細胞H23 cells,過度表現B55α會造成EGF刺激的Akt磷酸化位點Thr308和Ser473的磷酸化有明顯降低的影響。相反的,在過度表B56γ3不只造成較早的最高磷酸化程度出現,也有使EGF刺激的Akt磷酸化位點Thr308和Ser473的磷酸化有增加的趨勢。在HeLa cells中,過度表現B55α或是B56γ3,對在EGF刺激Akt磷酸化的位點Thr308的磷酸化造成稍微的降低或是沒有影響;然而過度表現B55α或是B56γ3,對於Akt磷酸化位點Ser473的磷酸化則都有增加的影響並且會影響到最高磷酸化的提早出現。我們接著也去分析過度表現B55α和B56γ3對NIH3T3、3T3-L1、H23和HeLa中,細胞生長的影響,我們發現在上述的細胞株之中,過度表現B55α和B56γ3都會對這些細胞的生長有抑制的作用。我們更進一步的去研究這些不同的調節次單元對於細胞週期的影響。我們發現當過度表現B56γ3而非B55α在NIH3T3 cells,會延遲細胞週期在G1到S期的進行。另外我們也發現,NIH3T3有過度表現B56γ3 的細胞,從G1到S時期,有比較高的p27kip1的表現量,然而在過度表現B55α則沒有和B56γ3一樣有明顯的趨勢。總而論之,我們的研究結果指出,不同的調節次單元在PP2A調節細胞生長的訊息傳遞以及細胞週期的調節角色之不同。
PP2A, protein phosphatase 2A, is one of the major serine/threonine phosphatases in many cellular processes. A PP2A holoenzyme comprises three subunits, including a 36 kDa catalytic subunit (PP2A/C), a 65 kDa scaffold subunit (PP2A/A), and a third variable regulatory subunit (PP2A/B). B subunits are believed to control substrate specificity and subcellular localization of PP2A, and there are at least four families of the B subunit, named B, B’, B’’, B’’’. Our lab has previously found that the PP2A AB55αC holoenzyme interacts with Akt, and selectively dephosphorylates Thr308 but not Ser473 of the Akt. Here we investigate two distinct B regulatory subunits, B55α and B56γ3, in various functional aspects including AKT activation, cell growth, and cell cycle progression in several cell types. Consistent with our previous report, in both NIH3T3 and 3T3-L1 cells, overexpression of B55α but not B56γ3 resulted in significant reduction of serum stimulated AKT phosphorylation at Thr308. In human lung cancer H23 cells, overexpression of B55α resulted in significant reduction of EGF-stimulated Akt phosphorylation at both Thr308 and Ser473. Conversely, overexpression of B56��3 resulted in not only earlier peak but also higher level of EGF-stimulated Akt phosphorylation at both Thr308 and Ser473. In HeLa cells, overexpression of B55α or B56��3 caused modest effect on EGF-stimulated Akt phosphorylation at Thr308. However, overexpression of B55α or B56��3 resulted in earlier peak and higher phosphorylation level at Ser473. Next, we analyzed the effect of overexpression of B55α and B56γ3 on cell proliferation in NIH3T3, 3T3-L1, H23 and HeLa cells, and we found that overexpression of B55α or B56γ3 inhibited cell proliferation of all cell types examined. We further investigated the role of these distinct B subunits in cell cycle, and found that overexpression of B56γ3 but not B55α delayed G1 to S progression of the cell cycle in NIH3T3, whereas B55α shows modest effects. Furthermore, during G1 to S progression, 3T3 cells with B56γ3 overexpression but not B55α have the higher protein level of p27kip1. Taken together, our results demonstrate distinct regulatory B subunits function differently in regulating PP2A activity to control cell growth signaling and cell cycle.
【目錄】 1
【縮寫對照表】 5
【英文摘要】 6
【中文摘要】 8
【緒論】 10
【一. Akt,又稱蛋白激酶B】 10
【二. 蛋白磷酸酶PP2A】 11
【三. PP2A結構性次單元—PP2A/A】 12
【四. PP2A催化性次單元—PP2A/C】 12
【五. PP2A調節性次單元—PP2A/B】 13
【B(B55)家族】 13
【B’(B56/61)家族】 13
【B’’(B46/59/72/130)家族】 14
【B’’’(B93/110)家族】 14
【六.PP2A對細胞週期的影響】 15
【七.細胞週期調控蛋白─p27】 15
【實驗材料及方法】 17
【一. 抗體及試劑】 17
【二. 細胞培養】 17
(一) 血清刺激 17
(二) Insulin刺激 18
(三) EGF刺激 18
【三. 反轉錄病毒的製備(retroviral preparation)】 18
【四. 反轉錄病毒感染(retroviral infection)】 19
(一) NIH3T3或3T3-L1細胞 19
(二) HeLa或H23細胞 19
【五. 篩選穩定表現HA or FLAG-tagged B55�恁BHA or FLAG-tagged B56γ3、或vector only的細胞】 20
【六. 西方墨漬法】 20
【七. 細胞週期同步化 (synchronization) ─ serum starvation法】 20
【八. 細胞週期同步化 (synchronization) ─ double thymidine block】 21
【九. 細胞週期同步化 (synchronization) ─ 接觸抑制生長(contact inhibition)】 21
【十. 流式細胞儀分析 (BrdU + PI staining)】 22
【實驗結果】 23
【一、在NIH3T3 cells中,PP2A/B55α完全酶和PP2A/B56γ3完全酶會減緩細胞增殖,而且對於Akt活性有不同的調節作用】 23
【二、在3T3-L1 cells中,PP2A/B55α完全酶和PP2A/B56γ3完全酶會減緩細胞增殖,而且對於Akt活性有不同的調節作用】 24
【三、在H23 cells中,PP2A/B55α完全酶和PP2A/B56γ3完全酶會減緩細胞增殖,而且對於Akt活性有不同的調節作用】 24
【四、在HeLa cells中,PP2A/B55α完全酶和PP2A/B56γ3完全酶會減緩細胞增殖,而且對於Akt活性有不同的調節作用】 25
【五、PP2A/B55α完全酶對細胞週期的進行的影響】 25
【六、PP2A/B56γ3完全酶會延遲細胞週期G1到S phase的進行】 26
【七、PP2A/B56γ3完全酶對於細胞週期的進行從G1到S時期的延遲,可能經由調控p27kip1所造成】 27
【結論】 28
【討論】 30
【一、不同的調節次單元對於PP2A調控Akt的角色不同】 30
【二、PP2A不同的調節次單元對於細胞週期的調控機制不同】 30
【三、不同的B調節次單元影響細胞的抗壓性】 31
【四、B56γ3對細胞週期進行調控的影響程度會因細胞週期同步化方法不同而有差異】 32
【五、B55α在細胞週期調控上的角色】 32
【六、p27kip1的磷酸化和其穩定性之關係】 33
【圖】 34
圖一、過度表現B55α或B56γ3對於NIH3T3細胞在增殖上的影響 35
圖二、B55α和B56γ3過度表現對NIH3T3細胞存活率的影響 36
圖三、在NIH3T3細胞中,過度表現B55α或B56γ3對於Akt磷酸化的影響 37
圖四、過度表現B55α或B56γ3對於3T3-L1細胞在增殖上的影響 38
圖五、B55α和B56γ3過度表現對3T3-L1細胞存活率的影響 39
圖六、在3T3-L1細胞中,過度表現B55α或B56γ3對於Akt磷酸化的影響 40
圖七、過度表現B55α或B56γ3對於癌細胞H23在增殖上的影響 41
圖八、B55α和B56γ3過度表現對H23細胞存活率的影響 42
圖九、在H23細胞中,過度表現B55α或B56γ3對於Akt磷酸化的影響 43
圖十、過度表現B55α或B56γ3對於癌細胞HeLa在增殖上的影響 44
圖十一、B55α和B56γ3對HeLa細胞存活率的影響 45
圖十二、在HeLa細胞中,過度表現B55α或B56γ3對於Akt磷酸化的影響 46
圖十三、過度表現B55α對於NIH3T3細胞在以血清刺激重新進入細胞週期的影響 47
圖十四、在NIH3T3細胞中,過度表現B56γ3對於細胞在以血清刺激重新進入細胞週期的影響 48
圖十五、將圖(十四) BrdU染色的部份的圖量化之後所得的結果 49
圖十六、將圖(十四) PI染色的部份的圖量化之後所得之結果 50
圖十七、在NIH3T3細胞中,過度表現B56γ3對於細胞週期的的影響 51
圖十八、將圖(十七) PI染色的部份的圖量化之後所得之結果 52
圖十九、偵測在NIH3T3細胞中由接觸抑制法釋放後再度進入細胞週期後,過度表現B56γ3對於p27kip1表現量的影響 53
圖二十、在血清刺激後重新進入細胞週期的NIH3T3細胞中,偵測蛋白質測定,觀察過度表現B56γ3對於p27kip1表現量的影響 54
圖二十一、在NIH3T3細胞中,過度表現B55α對於細胞週期的的影響 55
圖二十二、將圖(二十一) PI染色的部份的圖量化之後所得的結果 56
圖二十三、分析在NIH3T3細胞中,由接觸抑制生長法釋放後再度進入細胞週期時,過度表現B55α對於p27kip1表現量的影響 57
圖二十四、過度表現B55α對於3T3細胞在以血清刺激重新進入細胞週期的影響 58
圖二十五、將圖(二十四) PI染色的部份的圖量化所得之結果 59
圖二十六、圖(二十四)的蛋白質測定,偵測在NIH3T3細胞中,由低血清培養同步後,用血清刺激再進入細胞週期時,過度表現B55α對於p27kip1表現量的影響 60
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