臺灣博碩士論文加值系統

中文摘要
葡萄糖六磷酸去氫酵素在維持細胞中氧化還原平衡扮演重要角色。本論文第一部份茲以缺乏葡萄糖六磷酸去氫酵素之細胞株HFF1探討此酵素在有核細胞之作用。首先HFF1細胞呈現生長遲緩現象。從細胞流體分析結果亦顯示此細胞隨代數增加G1細胞比例快速增加。細胞形態出現老化的特徵：細胞外形呈扁平狀；老化相關的半乳糖酵素(SA-b-Gal)表現增加。且細胞週期抑制分子 p16 (INK4a)、p21 (CIP1) 和 p53 亦有增加。但HSP27和 HSP70量則減少。吾人以外來葡萄糖六磷酸去氫酵素基因送入細胞內表現時，則可以防止此細胞出現生長遲緩和過早老化現象。吾人以DCF染色法得知氧化壓力可能使得細胞過早老化。吾人欲研究老化過程機轉，故嘗試使用基因晶片技術來探討在正常和缺乏葡萄糖六磷酸去氫酵素之細胞株老化時所伴隨之基因表現變化。
本論文第二部份以探討cAMP與MEKK在T細胞活化中的角色。cAMP 可通過抑制細胞介素(cytokine)如淋巴介素二(interleukin 2, IL2)的轉錄來抑制免疫反應。在淋巴介素二(interleukin 2, IL-2)的啟動子上，cAMP通過干擾NF-kB活化來達成其效果。最近吾人發現cAMP亦能抑制JNK的活性。由於JNK在T細胞活化上扮演不可或缺之角色。故吾人欲探討cAMP、JNK和NF-kB活化之間關係。DMEKK的表現可在細胞活化NF-kB的活性，MEK的表現則無此效果。況DMEKK的表現可改變cAMP對NF-kB活化。故cAMP的目標分子可能位於MEKK之上游。且cAMP的抑制效能且受轉錄及轉譯抑制劑影響。吾人推測：cAMP誘導調節性分子的合成，此一分子抑制MEKK/SEK/JNK路徑，從以調控NF-kB的活性。

英文摘要
The first part of the thesis is concerned with the effect of glucose-6-phosphate dehydrogenase (G6PD) deficiency on the physiology of nucleated cells. Glucose-6-phosphate dehydrogenase (G6PD) is involved in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and the maintenance of the cellular redox balance. Biological effects of G6PD were studied using G6PD-deficient human foreskin fibroblasts (HFF). Cell growth parameters, namely, the growth rate and cell cycle profile, were examined in a primary G6PD-deficient cell strain and its normal counterpart. In contrast to that of normal HFF, the doubling time (DT) of G6PD-deficient cells increased steadily from population doubling level (PDL) 15 to 63. This was accompanied by a significant increase in the percentage of G1 cells. The slowdown in growth preceded an early entry of these cells into a non-dividing state reminiscent of cellular senescence. These cells exhibited signs of aging as indicated by large, flattened morphology and senescence-associated b-galactosidase (SA-b-gal) staining. The levels of the cell cycle inhibitor p16 (INK4a) and p21 (CIP1), and the tumour suppressor p53 increased during the process. Meanwhile, an opposite trend was observed in the level of molecular chaperones HSP27 and HSP70. These molecular changes are characteristic of senescent cells. The importance of G6PD activity in cell growth was corroborated by the finding that ectopic expression of active G6PD in the deficient cells prevented their growth retardation and early onset of senescence. Mechanistically, the enhanced fluorescence in dichlorofluorescin (H2DCF)-stained G6PD-deficient cells suggests the possible involvement of reactive oxygen species in senescence. When tested for their sensitivities to a sub-lethal oxidative insult, HFF1 exhibited an increased susceptibility to induction of senescent phenotypes. Taken together, our results show that G6PD deficiency predisposes human fibroblasts to retarded growth and accelerated cellular senescence. Moreover, our G6PD-deficient HFF is envisaged as a model system to delineate the effects of redox alterations on cellular processes.
To gain an insight into the mechanistic aspects of senescence, we examined the genes that were differentially expressed during the normal senescence of HFF3 and the accelerated senescence of HFF1. Analysis was still in progress to illuminate the epi- and genetic changes accompanying senescence.
The second part of the thesis is dealt with the role of MEKK in T cells, using cAMP as a probe for the mechanism of T cell activation. cAMP exerts its effect by inhibition of specific kinases and transcription factors responsible for expression of cytokines, such as IL-2 which play essential roles in activation process. It has been observed that cAMP suppresses IL-2 production at transcriptional level. Of cis-regulatory elements on IL-2 promoter, only the NF-kB site but not the AP-1, Oct nor NF-AT sites is target of suppressive effect of cAMP. However, the upstream signalling pathway involved in NF-kB activation and the step at which cAMP inhibits remain elusive. Recently, it has been shown that cAMP antagonizes c-Jun N-terminal kinase (JNK) while it leaves mitogen activated protein kinase (MAP) almost unaffected. This prompts us to examine the possibility whether JNK pathway is involved in NF-kB activation. Expression of constitutively active form of MAPK kinase kinase, △MEKK, the activator of JNK pathway, induced NF-kB in EL4 cells. On the contrary, expression of MAPK kinase, MEK, did not stimulate NF-kB activity. Interestingly, △MEKK expression did not augment AP-1 activity in EL4 cells, even though it could induce JNK activation, as assayed by phosphorylation of exogenous c-Jun substrate. Unlike most of other transcriptional factors acting on IL-2 promoter, NF-kB does not require dual signals for activation. These findings suggest that NF-kB is specifically and distinctly activated by the MEKK/SEK/JNK cascade. This notion was supported by the fact that expression of △MEKK was able to reverse the effect of cAMP on NF-kB activation. Furthermore, it places MEKK downstream of molecular target of cAMP. Observation that the inhibitory effect of cAMP showed sensitivity to cycloheximide and actinomycin D is intriguing. It is likely that a regulatory molecule is produced in response to cAMP and negatively modulates the MEKK/SEK/JNK pathway. Identification of such regulator will contribute much to our understanding of regulation of MEKK/SEK/JNK cascade.
第一部份
第一部份摘要-------------------------------------------------------------- 04-05頁
第一章
緒論---------------------------------------------------------------------------- 07-08頁
材料與方法------------------------------------------------------------------- 09-13頁
結果---------------------------------------------------------------------------- 14-20頁
討論---------------------------------------------------------------------------- 21-27頁
參考文獻---------------------------------------------------------------------- 28-37頁
圖表---------------------------------------------------------------------------- 38-61頁
第二章
緒論---------------------------------------------------------------------------- 63-64頁
材料與方法------------------------------------------------------------------- 65-66頁
結果---------------------------------------------------------------------------- 67-69頁
討論---------------------------------------------------------------------------- 70-71頁
參考文獻---------------------------------------------------------------------- 72-74頁
圖表---------------------------------------------------------------------------- 75-86頁
第三章
緒論---------------------------------------------------------------------------- 88-89頁
材料與方法------------------------------------------------------------------- 90-92頁
結果---------------------------------------------------------------------------- 93-98頁
討論---------------------------------------------------------------------------- 99-100頁
參考文獻---------------------------------------------------------------------- 101-103頁
圖表---------------------------------------------------------------------------- 104-127頁
第一部份縮寫表------------------------------------------------------------- 128-129頁
第二部份
第二部份摘要---------------------------------------------------------------- 132-133頁
緒論---------------------------------------------------------------------------- 134-142頁
材料與方法------------------------------------------------------------------- 143-148頁
結果---------------------------------------------------------------------------- 149-153頁
討論---------------------------------------------------------------------------- 154-157頁
參考文獻---------------------------------------------------------------------- 158-167頁
圖表---------------------------------------------------------------------------- 168-188頁
縮寫表------------------------------------------------------------------------- 189頁

封面
總目錄
授權書
論文指導委員名冊
指導教授推薦書
博士論文審定書
誌謝
圖表目錄
中文摘要
英文摘要
附錄
第一部份
第一部份摘要
第一章
緒論
材料與方法
結果
討論
參考文獻
圖表
第二章
緒論
材料與方法
結果
討論
參考文獻
圖表
緒論
材料與方法
結果
討論
參考文獻
圖表
第一部份縮寫表
第二部份
第二部份摘要
緒論
材料與方法
結果
討論
參考文獻
圖表
縮寫表
其他

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