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系統識別號 U0026-2211201920291100
論文名稱(中文) 探討磷酸水解酶PP2A的調節次單元B55δ在調控STOML2磷酸化及活性所扮演的角色
論文名稱(英文) Investigate the Role of the B55δ Regulatory Subunit of Protein Phosphatase 2A in Regulating Phosphorylation and Activities of STOML2
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 107
學期 2
出版年 108
研究生(中文) 楊庭伃
研究生(英文) Ting-Yu Yang
學號 T16064085
學位類別 碩士
語文別 英文
論文頁數 98頁
口試委員 指導教授-蔣輯武
口試委員-吳梨華
口試委員-凌斌
中文關鍵字 PP2A-B55δ完全酶  磷酸化蛋白電泳分析方法  粒線體定位 
英文關鍵字 PP2A-B55δ holoenzyme  STOML2  Phos-tagTM SDS-PAGE Phos-tagTM SDS-PAGE  mitochondrial localization 
學科別分類
中文摘要 蛋白磷酸酶2A型 (簡稱PP2A) 是主要的絲氨酸/蘇氨酸磷酸酶之一,並在真核細胞中廣泛表達。PP2A由三個次單元所組成,包含結構性次單元A,催化性次單元C,以及決定受質特異性和細胞座落位置的調節性次單元B。B調節次單元可以分為四個家族,B (B55 / PR55),B' (B56 / PR61),B' (PR72 / PR130)和B' (PR93 / SG2NA)。我目前的研究重點是屬於B (B55 / PR55)家族的B55δ,B55δ除了在調節有絲分裂的進入和出離發揮關鍵作用外,最近研究也顯示出B55δ在調節腫瘤中浸潤性T細胞的存活和生長扮演負面角色。STOML2是一種粒線體蛋白,也稱為SLP-2和paratarg-7,可調節粒線體的生合成。STOML2的表達在多種癌症中是高度表現的,並會促進腫瘤細胞的腫瘤發生、轉移和侵襲。另外,STOML2在調節T細胞受體信號傳導和T細胞活化中也具重要作用。已知PP2A-B55δ完全酶會去磷酸化STOML2,而PP2A-B55δ和STOML2之間相互作用失調是漿細胞疾病的標誌之一。重要的是,PP2A-B55δ在調節STOML2的磷酸化中的功能作用在很大程度上是未知的。
我們首先研究B55δ在調節STOML2的蛋白質和磷酸化水平中所扮演的角色。 在一般恆定狀態下或血清刺激後的HeLa及Jurkat細胞中,B55δ穩定降低表現或過度表達對STOML2的表現沒有顯著影響。Phos-tagTM SDS-PAGE分析的結果顯示當B55δ穩定降低表現時會增加磷酸化形式的STOML2表現。此外,利用共同表達PKC ζ及用PKC ζ活化劑PMA處理,我們確認了受PKC ζ催化磷酸化後的STOML2在Phos-tagTM SDS-PAGE分析呈現的異構型分子,而且我們也發現PKC ζ催化磷酸化的STOML2分子會選擇性地被B55δ調降,而不是透過B56γ3。為了研究B55δ調控STOML2對粒線體的生物性功能,我們透過高解析率螢光顯微鏡研究了粒線體相對數量和STOML2在細胞中的分佈。結果顯示STOML2增加了粒線體的量,但共同表現B55δ或B56γ3時則降低了STOML2對粒線體量的增強作用。此外,我們發現內生性及外生性STOML2皆呈點狀分佈,但當B55δ或B56γ3過度表達時,造成外生性STOML2則形成細胞質中的聚集體。透過共定位分析,B55δ的過度表達會輕微影響內生性STOML2的座落位置,但過度表現B55δ或B56γ3會嚴重地破壞外生性STOML2在粒線體座落位置。
綜合以上,我們的結果顯示在HeLa和Jurkat細胞中,無論是穩定狀態還是血清刺激下B55δ的過度表達或降低表現皆對STOML2的表現沒有顯著影響。在磷酸化調節中,B55δ是主要調降PKC ζ誘導的STOML2磷酸化。此外,B55δ及B56γ3皆減少了STOML2對粒線體數量的增強作用並干擾外生性STOML2的粒線體分佈。
英文摘要 Protein phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases and widely expressed in eukaryotic cells. A PP2A holoenzyme consists of three subunits including a scaffolding A subunit, a catalytic C subunit, and a variable regulatory B subunit, which determines the substrate specificity and subcellular localization of PP2A. The B regulatory subunit has been classified into four subfamilies, B (B55/PR55), B’ (B56/PR61), B’’ (PR72/PR130), and B’’’ (PR93/SG2NA). The current study focused on B55δ, which belongs to the B (B55/PR55) family. In addition to playing a key role in regulating entry and exit of mitosis, B55δ was recently shown to play a negative role in regulating survival and proliferation of tumor-infiltrating T cells. STOML2, also known as SLP-2 and paratarg-7, is a mitochondrial protein and regulates the biogenesis and activities of mitochondria. Expression of STOML2 is upregulated in a variety of cancer and promotes tumorigenesis, migration and invasion of tumor cells. Additionally, STOML2 plays an important role in regulating T cell receptor signaling and T cell activation. The PP2A-B55δ holoenzyme was shown to dephosphorylate STOML2, and the dysregulated interaction between PP2A-B55δ and STOML2 is one of the hallmarks of plasma cell diseases. Importantly, the functional role of PP2A-B55δ in regulating reversible phosphorylation of STOML2 is largely unknown.
We firstly investigated the role of B55δ in regulating the protein and phosphorylation level of STOML2. In HeLa cells, overexpression or knockdown of B55δ had no significant impact on levels of STOML2 at steady state. Upon serum stimulation, the protein levels of STOML2 still remained unaffected by B55δ. Transiently transfection of B55δ or B55δ-specific shRNA also did not alter the STOML2 protein expression in HeLa cells. In addition, the protein expression of STOML2 was not affected in Jurkat cells with stable knockdown of B55δ expression. Results of Phos-tagTM SDS-PAGE analysis showed that knockdown of B55δ increased phosphorylation of STOML2. At steady state, at least three phosphorylated forms of STOML2 were identified, and levels of the phosphorylated form of STOML2 were significantly decreased by both B55δ and B56γ3. Furthermore, under co-expression of PKC ζ and PMA treatment, we identified two phosphorylated bands of STOML2 catalyzed by PKC ζ by Phos-tagTM SDS-PAGE analysis. The levels of one of the phosphorylated bands of STOML2 were more selectively decreased by B55δ than by B56γ3. To investigate whether the biological function of STOML2 on mitochondria is regulated by B55δ, we investigated the mitochondrial biogenesis regulated by B55δ using mitochondrial staining and fluorescence microscopy. The integrated density fluorescence analysis showed that transient STOML2 overexpression increased mitochondrial staining, and both exogenous B55δ and B56γ3 reduced the enhancement of mitochondrial staining by STOML2. Furthermore, we investigated whether the mitochondrial distribution of STOML2 is regulated by B55δ, and we found that endogenous STOML2 exhibits punctate distribution, while exogenous STOML2 formed cytoplasmic aggregates when B55δ or B56γ3 was overexpressed. By colocalization analysis, transient B55δ overexpression slightly affect mitochondrial localization of endogenous STOML2, but both B55δ and B56γ3 significantly impaired mitochondrial distribution of exogenous STOML2.
In summary, our results demonstrated that overexpression of B55δ had no effect on the protein level of STOML2 both at steady state and under serum stimulation in both HeLa and Jurkat cells. However, knockdown of B55δ expression also showed no effect on the protein level of STOML2 in both HeLa and Jurkat cells. Although both B55δ and B56γ3 reduced the level of certain phosphorylated forms of STOML2, B55δ selectively decreased levels of phosphorylated STOML2 catalyzed by PKC ζ activation compared to B56γ3. Interestingly, both B55δ and B56γ3 decreased STOML2-enhanced mitochondrial biogenesis and impaired mitochondrial localization of exogenous STOML2.
論文目次 中文摘要 III
Abstract V
致謝 VII
List of Contents IX
List of Tables XI
List of Figures XII
List of Abbreviations XIII
Introduction 14
Protein phosphatase 2A (PP2A) 15
The regulation of PP2A in cellular pathways 15
The role of PP2A in a number of diseases 16
The role of PP2A in T cell development and regulation 17
The B55δ regulatory subunit of PP2A 18
Stomatin-like protein 2 (STOML2) 19
B55δ regulates phosphorylation of STOML2 in MGUS/WM/MM patients 20
Hypothesis 22
Materials and Methods 24
Cell lines and cell culture 25
Antibodies and Reagents 25
DNA constructs 28
Reagents of DNA cloning 28
Retrovirus and Lentivirus preparation 31
Retrovirus and Lentivirus infection 31
Transfection by Lipofectamine 2000 (Invitrogen) 32
Immunofluorescence staining and fluorescence microscopy 33
Western Blotting 35
Zn2+ Phos-tagTM SDS-PAGE 35
Results 38
Overexpression of B55δ did not change the protein level of STOML2 at steady state or under serum stimulation in HeLa cells 39
The protein levels of STOML2 was not altered by B55δ-specific shRNA knockdown under steady state or serum stimulation in HeLa cells 39
B55δ knockdown in Jurkat cells did not cause changes in STOML2 protein level 40
Co-transfection of exogenous B55δ or B56γ3 with STOML2 into HeLa cells showed no impact on protein level of exogenous STOML2 by exogenous B55δ or B56γ3 40
The protein level of STOML2 was not changed by B55δ by PMA-stimulated PKC ζ activation 41
B55δ increased the phosphorylated forms of STOML2 by knockdown of B55δ 41
B55δ, but not B56γ3 selectively regulates the phosphorylation of STOML2 at steady state 42
PKC ζ phosphorylation of STOML2 is modulated by B55δ 42
Both B55δ and B56γ3 inhibited the function of STOML2 to regulate mitochondrial activity 43
Investigating the regulation of subcellular localization of STOML2 by B55δ 43
Conclusion 45
Discussion 47
B55δ selectively regulates the PKC ζ-catalyzed phosphorylation of STOML2, but not the protein level of STOML2 48
Both B55δ and B56γ3 attenuate the positive regulation of STOML2 on mitochondrial biogenesis 49
Ectopically expressed B55δ and B56γ3 markedly impaired the subcellular localization of STOML2 49
The application of Phos-tagTM SDS-PAGE in clinical samples 50
B55δ knockdown efficiency is a critical issue for conclusive effects on functions of STOML2 in cells 51
References 52
Figures 60
Appendix 92
作者簡歷 98
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