幽門螺旋桿菌會經由分泌不同的有毒因子，如LPS、CagA 與 VacA 等，可引起胃潰瘍或胃癌等疾病。其並可誘發MAPKs 傳遞路 徑之活化。SUMO-1 為泛激素相關修飾蛋白質的一員，然而其是否參與於幽門螺旋桿菌誘發的細胞凋亡機制並不清楚。先前本研究室以螢
光顯微鏡觀察RFP-SUMO-1 過度表現的胃癌細胞發現幽門螺旋桿菌可誘發RFP-SUMO-1 的過度表現及增加細胞凋亡的趨勢。除此之外，我們也發現幽門螺旋桿菌的感染可增加細胞質的RFP-SUMO-1 的量且與細胞的凋亡有正相關性。因此本實驗繼續對SUMO-1 如何參與於幽門螺旋桿菌誘發的細胞凋亡之訊息傳遞途徑之加強做進一步的
探討。結果顯示幽門螺旋桿菌的感染可促使MAPKs 的活化，而且在過度表現RFP-SUMO-1 的細胞中，此情形更為明顯。但MAPKs 的活化似乎與細菌是否能分泌CagA 與VacA 並無關係。以MAPKs 抑制劑探討SUMO-1 在MAPKs 傳導路徑中角色的結果發現在過度表現RFP-SUMO-1 的胃癌細胞中，僅p38 抑制劑可以明顯的抑制由幽門螺旋桿菌所誘發的細胞凋亡。同時也發現在過度表現RFP-SUMO-1 的細胞中，p53 之mRNA 及蛋白的表現量較高。因此推測RFP-SUMO-1增強幽門螺旋桿菌誘發的細胞凋亡可能經由活化p38 之訊息傳遞途徑及加強p53 之表現而達成。此外，細胞過度表現RFP-SUMO-1 時
也會增加細胞核NF-κB 的量及COX-2 的表現。幽門螺旋桿菌感染時，核中NF-κB 之量會上升；細胞整體或一些細胞質的RFP-SUMO-1之量也上升。因此，本研究認為由幽門螺旋桿菌造成的細胞壓力可促使 SUMO-1 在細胞中的表現上升，藉由活化MAPK 的訊息傳導路徑，除了可以啟動促進細胞凋亡的p38-p53 路徑的活化之外，同時亦可啟動抑制細胞凋亡的ERK-NF-κB-COX2 路徑之活化。但是，細胞如何做凋亡或生存最後決擇之詳細機轉，尚不是很清楚，值得再進一步研究。

Helicobacter pylori (H. pylori) causes peptic ulcer or gastric cancer through different virulence factors including lipopolysaccharides (LPS), the cytotoxin-associated gene A product (CagA), and vacuolating
cytotoxin A (VacA) etc. It stimulated mitogen-activated protein (MAP) kinase signaling cascades. Small ubiquitin-related modifier (SUMO) is a member of ubiquitin-related protein modifiers. However, the mechanisms of the involvement of SUMO-1 on H. pylori induced apoptosis were not clear. Our previous study showed that the expression of RFP-SUMO-1
and apoptosis were increased significantly by fluorescence microscopy assays on RFP-SUMO-1 transfectants during H. pylori infection. In addition, the cytoplasmic SUMO-1 was increased during infection and positively associated with apoptosis. Here, how SUMO-1 was involved in the apoptotic signaling enhancement during H. pylori infection was
studied. Results showed that H. pylori infection enhanced MAP kinase activation and the effects were stronger on the SUMO-1 overexpressed cells. However, it was not affected by the secretion of CagA or VacA toxins of H. pylori. To investigate the possible role of SUMO-1 on MAPKs mediated signaling pathways, three selective MAPKs inhibitors were used on RFP-SUMO-1 overexpressed cells. Only p38 inhibitor decreased the levels of apoptosis during H. pylori infection and the expression of p53 was increased on RFP-SUMO-1 1 overexpressed cells.
Thus, p38 and p53 pathways were suggested to be involved in SUMO-1 enhanced apoptosis during H. pylori infection. In addition, the nuclear localization of NF-κB and expression of COX-2 were enhanced on
RFP-SUMO-1 overexpressed cells. Moreover, more nuclear NF-κB and cytoplasmic as well as nuclear RFP-SUMO-1 were observed during H. pylori infection. Our data suggest that H. pylori infection enhances
SUMO-1 expression which activates MAPKs on both the pro-apoptotic p38-p53 pathway and the anti-apoptotic ERK-NF-κB-COX2 pathway. The detail mechanisms on how cells making the final decision on the survival or apoptosis were still not clear and deserving to investigate.

中文摘要……………………………………………………………… 1
英文摘要……………………………………………………………… 2
縮寫表………………………………………………………………… 3
一、緒論……………………………………………………………… 6
1. 幽門螺旋桿菌 (Helicobacter pylori)………………………….. 6
1.1 Cag Pathogenicity Island (Cag-PAI)………………………... 9
1.2 液泡式的毒素A (Vacuolating Cytotoxin A, VagA)………... 11
1.3 內毒素脂多醣 (Lipopolysaccharide, LPS).………………... 13
1.4 Blood group antigen-binding adhesion (BadA)……………… 15
1.5 幽門螺旋桿菌與細胞凋亡的關係………………………….. 15
2. 相撲蛋白(Small ubiquitin-related modifers, SUMOs)………….. 17
2.1 SUMO-1與泛激素(Ubiquitin).……………………………… 17
2.2 相撲化 (Sumoylation)………………………………………. 18
2.3 SUMO-1在細胞中的位置…………………………………... 19
2.4 SUMO-1在細胞中的功能…………………………………... 20
2.4.1 調控核體的組成……………..………………………... 20
2.4.2 調控蛋白質在細胞中的位置…………………………. 21
2.4.3 調控蛋白質活性與穩定性…………………………….
2.5 SUMO-1與細胞凋亡的關係………………………………... 23
26
3. MAPK pathway………………………………………………….. 27
3.1 Extracellular signal-related kinases (ERK1/2) signaling cascades……………………………………………………….
27
3.2 SAP kinase/JNK (c-Jun N-terminal kinase) signaling cascades……………………………………………………….
29
3.3 p38 signaling cascades……………………………………….. 30
二、 研究目的…………………………………………………………. 33
三、 實驗材料及方法…………………………………………………. 34
1. 細胞培養………………………………………………………… 34
2. 轉植相撲蛋白進入細胞中 (SUMO-1 transfection)…………… 36
3. 細菌感染 (infection)……………………………………………. 34
4. 蛋白質電泳與西方點墨法 (Western blots, WB)…….………… 39
5. 免疫螢光染色 (Immunofluorescence)………………………... 44
6. 螢光顯微鏡分析 (fluorescence microscope analysis)………….. 46
7. Annexin-V assay…………………………………………………. 46
8. MAPK的抑制劑…………………………………………………
9. Reverse transcriptase PCR (RT-PCR)............................................. 46
47
四、結果………………………………………………………………… 51
1. H. pylori可誘發RFP-SUMO-1蛋白質表現的上升…………… 51
2. 過度表現的RFP-SUMO-1可增強MAPKs的活化…………… 53
3. 幽門螺旋桿菌之毒性分子對MAPKs活化的影響…………….. 56
4. RFP-SUMO-1對細胞凋亡與p38活化路徑的影響…………….. 58
5. SUMO-1可穩定p53 蛋白………………………………………. 62
6. RFP-SUMO-1對JNK與 ERK活化路徑的影響……………….. 65
7. 幽門螺旋桿菌及RFP-SUMO-1對NF-

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