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系統識別號 U0026-0812200914103591
論文名稱(中文) 探討Stat3訊息傳遞路徑在上皮細胞分化過程中對細胞聚滿所誘發之NHE3表達的調節機制
論文名稱(英文) Cell confluency-induced Stat3 activation regulates NHE3 expression during epithelial differentiation
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 蘇筱雯
研究生(英文) Hsiao-Wen Su
電子信箱 hsiaowensu@yahoo.com.tw
學號 s5892126
學位類別 博士
語文別 英文
論文頁數 127頁
口試委員 口試委員-沈孟儒
指導教授-湯銘哲
召集委員-蘇五洲
口試委員-賴明德
口試委員-洪文俊
口試委員-郭明良
中文關鍵字 訊息傳遞及轉錄因子3  細胞聚滿  細胞圓頂化  鈉氫離子交換蛋白3 
英文關鍵字 NHE3  Stat3  Slc9a3  Sp1  Sp3  cell confluency  dome formation 
學科別分類
中文摘要 過去的研究發現,細胞聚滿會誘導訊息傳遞及轉錄因子3 (Stat3) 在不同種癌細胞與上皮細胞中活化。然而其所調控之細胞功能與機制仍待進一步的釐清。許多上皮細胞當培養於二維平面時,隨著細胞逐漸聚滿(cell confluence),細胞分化(cell differentiation)現象會隨之出現並以細胞圓頂化(dome formation)的方式呈現。這是由於單層上皮細胞分化後造成上皮細胞兩側離子運輸蛋白(transepithelial transports)的極性化,使得鈉離子,氯離子及水分子的運輸機制被啟動。在本研究中,我們將利用腎臟上皮細胞 (MDCK), 乳腺上皮細胞 (NMuMG)及人類大腸癌上皮細胞 ( human Caco-2)來研究Stat3在細胞聚滿所誘發的細胞圓頂化中的詳細分子機轉。我們的研究發現,細胞聚滿所誘發的Stat3 活化時間早於細胞圓頂化的發生,而Stat3 可透由細胞核內的訊息傳遞來促進細胞的圓頂化。再者,當細胞大量表達活化態的Stat3 (Stat3-C)外源基因時可以增進細胞圓頂化與細胞中鈉氫離子交換蛋白3(sodium hydrogen exchanger 3,NHE3)的蛋白表現量。然而,細胞圓頂化與NHE3的蛋白表現量卻會被顯性抑制型的Stat3 (Stat3-F和Stat3-D)所抑制。同時,運用RNA干擾技術抑制細胞中Stat3表達量時,也觀察到相同的結果。此外,運用RNA干擾技術抑制細胞中NHE3的蛋白表達量或是處理NHE3活性抑制劑都會顯著抑制細胞圓頂化,顯示Stat3 可藉由調控NHE3 的蛋白表達量進而影響細胞圓頂化的發生。更進一步,我們發現Stat3 會藉由正向調控NHE3基因的轉錄而促進NHE3的蛋白表達量。為了釐清Stat3 調控NHE3基因轉錄的詳細分子機制,我們利用一系列不同長度的NHE3 promoter,找出Stat3對NHE3 promoter的調控區域主要座落於基因上游89到34核甘酸的位置,其中包含了重要轉錄因子Sp1/Sp3的可能蛋白結合位置,SpABC site。我們利用電泳遷移率分析實驗(EMSA)證實SpB site擁有比SpA site 更有效之Sp1/Sp3蛋白結合能力及啟動NHE3基因的誘導能力。雖然,細胞聚滿並不影響細胞核中Sp1/Sp3的蛋白表達量,但會誘導Stat3的蛋白活化及其於細胞核中的堆積量。更進一步藉由DNA親和性沈澱分析(DAPA)證明細胞聚滿會增強Stat3和Sp1/Sp3對NHE3 promoter上特定及獨立的轉錄因子結合位的蛋白結合力。免疫沈澱法更證明細胞聚滿會加強Stat3和Sp1/Sp3的蛋白結合性。此結果顯示Stat3藉由與Sp1/Sp3蛋白結合而參與在細胞聚滿所調控的NHE3基因轉錄上。另一方面,藉由Stat3 RNA干擾實驗及過度表達顯性抑制型外源Stat3基因之研究得知,細胞聚滿所增強的Sp1/Sp3與NHE3 promoter之間的蛋白-DNA結合力需要Stat3蛋白本身的直接參與。藉由核甘酸突變技術證實Stat3在NHE3 promoter上的轉錄因子結合位子是獨立於SpABC site的。綜合以上的實驗結果證實,細胞聚滿會誘發Stat3的活化及其進一步堆積於細胞核中,並與Sp1/Sp3形成蛋白複合體。此蛋白複合體與NHE3 promoter的結合形成啟動NHE3基因轉錄的必要條件。以上這些發現指出,細胞聚滿所誘發的Stat3/Sp1/Sp3訊息傳遞路徑,部分參與了NHE3基因轉錄的啟動,而因此促進細胞分化的發生。
英文摘要 Cell confluence induces the activation of signal transducer and activator of transcription-3 (Stat3) in various cancer and epithelial cells, yet the biological implications and the associated regulatory mechanisms remain unclear. Because confluent polarized epithelia demonstrate dome formation and sodium influx that mimic the onset of differentiation, we sought to elucidate the role of Stat3 in association with the regulation of selective epithelial transporters in this biological phenomenon by using model cells such as MDCK, NMuMG and Caco-2 cells. We first established the correlation between Stat3 activation events (Tyr705(P), nuclear translocation and specific DNA binding) and cell confluence-induced dome formation. Confocal microscopy provided evidence showing specific localization of Stat3 Tyr705(P) in the nuclei of dome-forming cells at initial stages. The relationship was further elucidated by the establishment of tetracycline-inducible expression of constitutive Stat3 mutant (Stat3-C) in MDCK cells. Dome formation was promoted by the expression of Stat3-C. In contrast, dome formation was inhibited while inhibition of Stat3 in cells with expression of either dominant negative Stat3 mutants (Stat3-F and Stat3-D) or Stat3 siRNA. One of the epithelial transporters, sodium hydrogen exchanger-3 (NHE3), was found to be increased during cell confluence. Interestingly, NHE3 expression could be up-regulated by Stat3-C but inhibited by Stat3-D through promoter regulation. Application of NHE3 shRNA and NHE3 inhibitors (EIPA and S3226) suppressed confluence-induced dome formation. These results demonstrated a cell confluence-induced Stat3 signaling pathway in epithelial cells in triggering dome formation through NHE3 augmentation.
The detail regulation mechanism of Stat3 on NHE3 gene transcription was studied by using serial promoter deletion analysis. We found that Stat3-responding element of rat NHE3 promoter that contained SpABC sites was localized at position -89 nt to -34 nt. EMSA results showed that SpB (-58/-55 nt) site was more efficiently than SpA (-72/-69 nt) site for both Sp1/Sp3 binding and the NHE3 promoter induction. DNA affinity precipitation assay further showed that cell density triggered specific and independent binding of Stat3 and Sp1/Sp3 on the NHE3 promoter, with an increase of the nuclear translocation and accumulation of Stat3 but without affecting on the protein levels of Sp1 and Sp3. Immunoprecipitation studies showed that the interaction of Stat3 with Sp1 and Sp3 was enhanced by cell density. These results suggested that the interaction of Stat3 with Sp1/Sp3 was involved in the cell density-mediated NHE3 promoter regulation. Moreover, the increase of cell density-induced Sp1/Sp3 binding and the NHE3 promoter activity were prevented by knocking down Stat3 using siRNA in Caco-2 cells or inhibition of Stat3 activity by stable expression of Stat3-D in MDCK cells. On the other hand, mutation of SpABC sites abolished the binding of Sp1 and Sp3, but not Stat3, to NHE3 promoter, indicating that Stat3 binding to NHE3 promoter is independent of Sp1 and Sp3. These results demonstrated that high cell density triggers Stat3 nuclear translocation to form a complex with Sp1 and Sp3, and the complex thereby triggers cell density-mediated NHE3 gene transcription.
In conclusion, we have identified a novel Stat3/Sp1/Sp3 signaling mechanism which participates in cell density induced in NHE3 gene transcription and subsequent epithelial cell dome formation.
論文目次 Contents------------------------------------------------- 1
Table contents--------------------------------------------4
Figure contents-------------------------------------------5
Abbreviations---------------------------------------------7
摘要------------------------------------------------------8
Abstract-------------------------------------------------10
Chapter 1 Introduction
1-1 The epithelia function in vivo------------------12
1-2 “Dome” is the in vitro character of transporting epithelial cells-----------13
1-3 Molecules that influence dome formation---------13
1-4 Dome formation is associated with epithelial differentiation from development to disease--------------15
1-5 Sodium/hydrogen exchangers (NHEs) family--------15
1-5.1 The fundamental functions of NHE proteins in cell biology----15
1-5.2 The biochemical characteristics of NHE protein--16
1-5.3 The specific location of NHEs-------------------17
1-5.4 The biologic function of NHEs-------------------18
1-5.5 The regulation mechanisms of NHE3---------------19
1-5.6 Sp1/Sp3 is important for sodium butyrate-mediated NHE3 promoter activity-----------------------------------20
1-6 The SP family in gene transcription regulation--21
1-7 The signal transducers and activators of transcription (STAT) family----22
1-7.1 The activation of the STAT signaling pathway----23
1-7.2 The mechanism of STAT-mediated transcriptional activation---24
1-7.3 Negative Regulation of STATs--------------------25
1-7.4 The biologic function of STATs------------------26
1-8 Hypothesis--------------------------------------26
Chapter 2 Materials and Methods
2-1 Cell lines and cultures-----------------------------29
2-2 Establishment of tetracycline inducible system and stable transfectants--29
2-3 Preparation of whole cell lysates, cytoplasmic and nuclear extracts------31
2-4 Reverse transcription-polymerase chain reaction (RT-PCR)---------------31
2-5 DNA affinity precipitation assay (DAPA)-------------32
2-6 Electrophorisis mobility shift assay (EMSA)---------32
2-7 Transfection and dual luciferase assay--------------33
2-8 RNA interference system-----------------------------34
2-9 Immunofluorescence and confocal study---------------35
2-10 Immunoprecipitations and Western blotting----------36
2-11 Statistics-----------------------------------------36
Chapter 3 Cell confluence-induced activation of Stat3 triggers epithelial dome formation via augmentation of NHE3 expression
3-1 Abstract-------------------------------------------38
3-2 Introduction---------------------------------------40
3-3 Results--------------------------------------------44
3-4 Discussion-----------------------------------------54
Chapter 4 Cell confluency-induced Stat3 activation regulates NHE3 expression by recruiting Sp1 and Sp3 to the proximal NHE3 promoter region during epithelial dome formation
4-1 Abstract-------------------------------------------59
4-2 Introduction---------------------------------------61
4-3 Results--------------------------------------------65
4-4 Discussion-----------------------------------------73
Chapter 5 Discussion
5-1 Possible role of Stat3 in the regulation of cell confluency-dependent dome formation----------------------78
5-2 Cell density is critical for Stat3/Sp1/Sp3 signaling on the up-regulation of NHE3 gene transcription during epithelial dome formation -------------------------------79
5-3 The Stat3/Sp1/Sp3 signaling pathway in gene regulation during epithelial dome formation--------------80
5-4 Possible role of Stat3/NHE3 signaling in the epithelial differentiation and transporting function ----80
5-5 Possible upstream molecules for cell confluence-mediated Stat3 activation during epithelial differentiation----------------------------------81
Chapter 6 Summary--------------------------------------83
References-----------------------------------------------86
Tables --------------------------------------------------99
Figures ------------------------------------------------102
Publications--------------------------------------------124
Manuscripts in preparation------------------------------125
Curriculum Vitae----------------------------------------126
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