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研究生:莊漢英
研究生(外文):Han-Ying Jhuang
論文名稱:人類Nap1蛋白之酵素活性與生長抑制效果
論文名稱(外文):Enzyme Activities and Growth Inhibitory Effects of Human Nap1
指導教授:簡靜香簡靜香引用關係
指導教授(外文):Chin-Hsiang Chien
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
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:97
中文關鍵詞:細胞週期蛋白質交互作用生長抑制
外文關鍵詞:Cell CycleNap1Growth ControlProtein-Protein Interaction
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神經胺酸水解酶相關蛋白(Neuramidase Associated Protein, Nap1)是一個新穎的人類蛋白,對於腈水解酶具有相當高的同質性。腈水解酶在低等生物中,能將醯胺水解為酸和氨,植物種子發育所需要的植物性賀爾蒙的生合成,而在化學工業中,能溫合、乾淨、並高選擇性地降解原先非生物可降解的化學物,因此無論在低等生物,或是化學工業中,皆扮演了重要的角色。因此,由於其可作為工業化學品的生物觸酶,使得腈水解酶受到相當的重視。有趣的是,腈水解酶基因序列在人類、線蟲、和果蠅內仍然具高保留性。在人類中,另一個腈水解酶同源蛋白¬─腈水解酶同源蛋白1(Nitrilase Homolog 1, Nit1)已被鑑定出,其與Fhit相似並同為抑癌蛋白。雖然Nit1已被鑑定為抑癌蛋白,但Nap1在人類內的角色卻仍然未明。是否Nap1在人體中仍具有酵素的功能,以及若是如此,那麼對人體的重要性為何,目前仍屬未知。此研究中,我們將已在胺基末端接上6個組胺酸標記的Nap1基因表現在大腸桿菌中,並使用接合上鎳原子的瓊脂糖凝膠純化出人類Nap1蛋白,再以丁醯胺酸作為受質,證明人類Nap1蛋白具有酵素活性。更進一步,我們發現過度表現Nap1基因的細胞顯示出生長受到抑制的現象。為了暸解這些現象,我們檢測了包括p53、p21和14-3-3σ等數個細胞週期調控蛋白在過度表現Nap1基因的細胞中表現量的變化。其中,我們發現一個重要的細胞週期調控蛋白,14-3-3σ在過度表現Nap1基因的細胞中有正調控的現象,而另一個S期的細胞週期素依賴激酶抑制劑1A/p21(Cyclin-Dependent Kinase Inhibitor 1A, CDK1A/p21)和腫瘤蛋白p53及其抑制者MDM2皆未有變化,僅管p53已知為14-3-3σ的上游調控蛋白。另外,調控細胞週期G2/M期的視網膜母細胞瘤蛋白Rb的磷酸化程度也在過度表現Nap1基因的細胞中有下降的現象,顯示Rb可能也參與在Nap1調控的生長抑制過程中。更進一步,我們發現Nap1能與Rb交互作用,顯示其磷酸化程度的降低可能與此交互作用有關。總結來說,這些結果可以提高我們對於Nap1的認識,而Nap1在人體中可能具有一個長期被低估的重要角色。
The neuramidase associated protein 1 (Nap1) is a novel human protein that shows high homology to nitrilase family. Nitrilases play important roles in lower organisms, as they hydrolyze amides to acids and ammonium and biosynthesize plant hormones required during seed development, and in industry, as they degrade otherwise bio-undegradable chemicals while the bioconversion is mild, clean, and highly selective. Nitrilases have accordingly gained much attention for its potential of being a biocatalyst for industrial chemical compounds. Intriguingly, nitrilase genes are highly conserved among species such as worm, fly, and human. In human, another nitrilase homolog have been identified – the nitrilase homolog 1 (Nit1), which functions as a tumor suppressor similar to Fhit. Whereas the human Nit1 has been identified as a tumor suppressor, functions of Nap1 remain elusive. Whether Nap1 drives enzymatic catalysis in human and, if true, the significance of it is still unknown. Here, by introducing C-terminally 6xHis-tagged human Nap1 gene into Escherichia coli (E.coli) and exploiting the nickel-charged sepharose gel system to purify the human Nap1 protein, we show that the Nap1 enzyme function is preserved in human as in lower organisms such as bacteria and plants using succinamic acid as the substrate. Further, we also show that Nap1-overexpressing cells exhibit growth inhibitory effects. To elucidate these effects, we examined the expression of several cell cycle regulators such as p53, p21, and 14-3-3σ. As a result, 14-3-3σ, a key cell cycle regulator, is upregulated in Nap1-overexpressing cells, while the S-phase regulator cyclin-dependent kinase inhibitor 1A (p21), or CDKN1A, and the tumor protein 53 (p53) and its inhibitor, MDM2, do not seem involved, in spite of the fact that 14 3 3σ is known to be a direct target of p53. In addition, phosphorylation form of the retinoblastoma protein (Rb), which regulates the G2/M cell cycle phase, is decrease in Nap1-overexpressing cells, indicating that Rb might as well participate in this effect. Furthermore, we show Nap1 interacts with Rb, suggesting that Nap1 might interfere Rb phosphorylation via interaction with it. Overall, these data could advance our understanding about Nap1, which may play a significant role that so far remain underestimated.
致謝 i
中文摘要 ii
ABSTRACT iv
目錄 vi
緒論 1
Nap1 1
Rb、E2F1、p53、p21、MDM2和14-3-3σ的細胞週期調控 3
Nap1純化與其酵素功能 7
藉由過度表現以研究Nap1蛋白功能增加 8
實驗材料 10
Bacterium 10
Cell Line 10
Plasmid 10
Culture Medium 11
Solution 12
Reagent 15
Enzyme 15
Antibody 16
Kit 16
Apparatus and Instrument 17
實驗方法 19
M2 Affinity Gel Purification 19
Agarose Gel Electrophoresis 20
Alamar Blue Assay 20
Bacterium Culture 21
Bacterial Protein Purification 21
Cell Culture 22
Protein G Co-Immunoprecipitation 23
Coomassie Blue Staining 24
Determination of Protein Concentration 24
Determination of Nucleic Acid Concentration 24
Plasmid Amplification 24
Protein Electrophoresis 25
Reverse Transcription Polymerase Chain Reaction 25
Total RNA Purification 26
Transfection 26
Transformation 27
Total Protein Extraction 27
Western Blotting 28
Enzyme Reaction 28
實驗結果 30
Protein purification of human Nap1 in E. coli system 30
Human Nap1 preserves the enzyme function as in lower organisms 30
Human Nap1 enzyme function is temperature sensitive 31
Enzymatic characterization of human Nap1 32
Nap1 mediates growth inhibitory effects in human 32
Nap1-mediated growth inhibitory effects are independent of Nap1 enzyme activities 33
14-3-3σ is upregulated in Nap1-overexpressing cells 33
Cyclin D1 is downregulated in Nap1-overexpressing cells 33
Rb phosphorylation levels are downregulated in Nap1-overexpressing cells 34
Expression levels of p53, p21, MDM2, and E2F1 are independent of Nap1 expression 34
Nap1 interacts with Rb 35
討論 36
Nap1具高保留性 36
人類Nap1的酵素功能 36
人類Nap1的生長抑制功能 37
Nap1同源蛋白的晶體結構 38
在腫瘤生成中的關聯 38
參考文獻 40
附表 55
附圖 61
附錄 80
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