臺灣博碩士論文加值系統

Notch 是個演化上具高度保留，穿過細胞膜一次的受體蛋白，在哺乳類的Notch 受體蛋白有Notch1∼4四種，被認為可調控基因的轉錄、細胞的增生、分化及早期細胞命運的決定，而Notch訊息傳遞的異常或突變會造成某些疾病的發生。當相鄰細胞表現的ligand 與Notch 受體蛋白的細胞外區域結合時，Notch 訊號傳遞系統就被活化，整個細胞內區域在靠近內膜處被蛋白分解脢切斷，而形成活化型Notch (Notch IC, 細胞內區域)。此活化型Notch會轉移至細胞核中，並且和一些可與DNA結合的轉錄因子，如：RBP-Jκ/CBF1，以及其他細胞因子結合，進一步調控標的基因的表現。所以這些參與的因子，對於Notch 訊息傳遞路徑影響甚巨。因此，為了進一步探討Notch 訊息傳遞路徑，本論文首要目標著重於探索參與Notch1 下游訊息傳遞路徑仍未知的結合因子，及初步分析這種結合所產生的生物功能。
本實驗參考葉添順老師與本實驗室先前利用GST-N1IC-ANK repeats之融合蛋白，與K562細胞萃取液混合，進行GST pull down Assay 來分析該細胞中有何蛋白質可與GST-N1IC-ANK融合蛋白做結合，並收集與融合蛋白結合的複合體，用2-D電泳及質譜儀分析此複合體的成員為何。在分析蛋白質體的數據中發現有數個候選蛋白質包括鋅手指蛋白的存在。分析比對之結果發現ZNF74的吻合度最高。ZNF74屬於C2H2 type的鋅手指蛋白。在其N端部份包含了一段稱為Krueppel-associated box (KRAB)的區域，在C端部份包含12個zinc finger motifs。具有KRAB 區域的蛋白主要功能到目前為止所知均具有抑制基因表現之功能，而zinc finger區域則是與特定的DNA序列做結合。因此本實驗有興趣繼續探討ZNF74與Notch 1之訊號傳遞是否有關。在實驗第一部份我們利用專一性引子以反轉錄聚合酶連鎖反應(RT-PCR)證實在K562細胞之中ZNF74基因是以isoform I存在。實驗第二部份，我們利用將HA-ZNF74基因植入表現N1IC的人類細胞HEK293，獲得細胞萃取液後再利用anti-HA或anti-N1IC抗體來進行共同免疫沉澱法(co-immunoprecipitation)反應，結果顯示ZNF74確實可以跟N1IC結合。為了更進一步找出ZNF74蛋白上是利用那個區域與N1IC做結合，我們利用可表現MBP融合的不同短縮型ZNF74之蛋白與表現N1IC或Ankyrin(Ank)的細胞萃取液混合。結果顯示，ZNF74的zinc finger區域與Ank的結合是必需的。實驗最後部份，我們利用SELEX(systematic evolution of ligands by exponential enrichment )來找出ZNF74結合的特定核苷酸序列為何。經過軟體序列比對結果相當複雜並無一致性。因此，根據上述的結果顯示，本實驗仍需要進一步的研究才能夠釐清在K562細胞中ZNF74蛋白參與Notch訊息傳遞下所扮演的生物角色為何。

Notch receptors are evolutionally highly conserved and play important roles in modulating cell fate decisions throughout the development from invertebrate to vertebrate species. Four homologues of Notch receptors have been identified in human and aberrant Notch signaling is associated with a number of human diseases. There is a consensus model of Notch signaling pathway containing multiple proteolytic steps. After ligand binding, Notch receptors are cleaved to release the intracellular domains of Notch receptors. The intracellular domains, the activated form of Notch receptors, are then translocated into nuclei and interact with other transcriptional machineries to regulate the expression of cellular genes.
In the previous data of Dr. Yeh and our lab, the proteomic study of GST-Notch1-Ank domain(GST-N1IC-Ank) pull down associated with cell lysate of erythrleukemia K562 cell, several zinc finger proteins were identified. Here, we wish to identify one of these zinc finger proteins, ZNF74, and characterize its biological function. The ZNF74 belongs to the family of Cys2-His2 type zinc finger proteins, it contains a KRAB repression domain at the amino- terminal region and 12 zinc finger motifs at carboxyl terminus. It has been showed that ZNF74 is localized to nucleus and the KRAB domain exhibits transcription repressor activity, whereas the Cys2-His2 zinc finger motifs recognized DNA sequence.
In this study, we designed to confirm the association between N1IC and ZNF74. The specific primers were synthesized and the RT-PCR result has shown that the ZNF74 transcript is splicing isoform I in the K562 cell. The mammalian expressing vector harboring HA-ZNF74 were transfected into HEK293 cells expressing N1IC, the cell lysate was prepared and immunoprecipitated by anti-HA or anti-N1-C-terminus antibody. The experiment showed that ZNF74 can associate with N1IC. For further dissecting the domains of ZNF74 associate with N1IC, we constructed different N- or C-terminal truncated ZNF74 fused to MBP protein for MBP pull down assay. The data showed that the zinc finger domain of ZNF74 is sufficient for binding with Ankyrin domain (Ank) of N1IC. The last part of this thesis, we tried to use SELEX (systematic evolution of ligands by exponential enrichment ) to find the target oligonucleotides binding sequence of ZNF74 protein. Due to the small sample size, the alignment data were complicated and difficult for interpretation. In conclusion, we still need more efforts to characterize the biological function of ZNF74 in K562 cell and to elucidate it’s relationship with Notch signaling pathway.

中文摘要………………………………………………………………………………i
英文摘要……………………………………………………………………………
目次……………………………………………..
第壹章、緒論…………………………………………………………………………1
一、Notch 訊息傳遞(Notch signaling pathway)…………………………… 1
二、鋅手指蛋白……………………………………………………………………4
第貳章、實驗材料與方法……………………………………………………………8
第一節、細胞培養…………………………………………………………………8
第二節、RNA 的分離(RNA isolation)………………………………………… 8
第三節、反轉錄聚合酶連鎖反應(reverse transcription polymerase
chain reaction)……………………………………………………… 8
第四節、質體之構築與PCR引子之採用…………………………………………9
第五節、瓊脂膠電泳(agarose gel electrophoresis)…………………………9
第六節、透析膜中抽取瓊脂膠內的DNA(DNA elution)…………………………10
第七節、接合反應(Ligation)……………………………………………………11
第八節、勝任細胞(Competent Cell)的製備……………………………………11
第九節、轉形做用(Transformation)……………………………………………12
第十節、微量質體DNA抽取(Plasmid Mini-Preparation)……………………14
第十一節、限制酶鑑定(Restriction Enzyme Digestion)……………………14
第十二節、細胞株的質體植入(Transfection)…………………………………15
第十三節、西方墨點分析法(Western blotting)………………………………15
第十四節、MBP融合蛋白質之表現………………………………………………17
第十五節、融合蛋白的純化………………………………………………………18
第十六節、MBP-fusion protein pull down assay……………………………19
第十七節、共同免疫沉澱法(Co-immunoprecipitation)………………………19
一、protein A sepharose 的製備……………………………………………19
二、protein A sepharose 與目標蛋白之抗體的結合………………………20
三、目標蛋白質的免疫沈澱……………………………………………………20
第十八節、SELEX(systematic evolution of ligands by
exponential enrichment )…………………………………………20
第參章、實驗結果……………………………………………………………………23第一節、以RT-PCR (Reverse transcription polymerase
chain reaction)來證明ZNF74基因是否存在於K562
細胞中………………………………………………………………… 23
第二節、表現質體之構築…………………………………………………………23
(一) 製備ZNF74-MF-3之DNA片段…………………………………………24
(二) 製備ZNF74-NR-M-7之DNA片段…………………………………………24
(三) 製備ZNF74-NR-1之DNA片段……………………………………………24
(四) 製備ZNF74之表現質體…………………………………………………24
(A)ZNF74-isoform-I-Full length之表現質體 ……………………… 24
(B)製備含NLS(Nucleus Localization Sequence)之表現質體…………25
(C)製備GST-ZNF74融合蛋白表現質體……………………………………25
(D)製備短縮型pcDNA-ZNF74-3Z、pcDNA-ZNF74-6Z、
pcDNA-ZNF74-9Z、pcDNA-ZNF74-12Z之表現質體……………………25
(E)製備MBP-ZNF74融合蛋白表現質體……………………………………26
第三節、 鑑定質體之表現 ………………………………………………………26
(一)表現質體在 COS-7 或 HEK293 細胞株中之表現…………………… 26
(二)融合蛋白表現質體在E. coli中之表現……………………………… 27
第四節、 利用共同免疫沉澱方式來證明N1IC與ZNF74之間的結合…………27
第五節、利用MBP 融合蛋白pull down assay來找出N1IC與ZNF74之
結合區域 ………………………………………………………………28
第六節、利用SELEX (systematic evolution of ligands by
exponential enrichment)方法找出 ZNF74及ZNF9 之特定DNA
結合序列 ………………………………………………………………29
第肆章、結果討論……………………………………………………………………31
第一節、ZNF74存在於K562細胞中………………………………………………31
第二節、利用共同免疫沉澱法 (co-immunoprecipitation) 與MBP融合
蛋白pull down assay證明ZNF74與Notch之間有結合關係，且
zinc finger motifs 7~9的位置是相互結合所必需的位置…………32
第三節、利用SELEX (systematic evolution of ligands by
exponential enrichment)所找出zinc finger protein結合核
苷酸之序列經比對(alignment)後的結果分析，序列複雜並無法
加以解釋……………………………………………………………… 33
參考文獻 ……………………………………………………………………………36
附表一、Lists of Primers in this study…………………………………… 46
附表二、Lists of constructed plasmids………………………………………47
附圖一、Schematic diagram of human Notch1 receptor and their variants..49
附圖二、Notch signaling pathway…………………………………………………50
附圖三、Sequences of ZNF74-isoform I. ZNF74 contains two
functional sub-domains: KRAB domain (nt 1-129) and zinc
finge domain (nt 528-1518)……………………………………………51
附圖四、Schematic diagrams of ZNF74 splicing isoforms................ 53
附圖五、Cloning strategy for full length cDNA of ZNF74 isoform I…… 54
附圖六、Step-by-step schematic diagram of construction of plasmids
harboring HA-tagged cDNA of ZNF74-I-full length……………… 55
附圖七、Constructions of different truncated and full length cDNA
fragment of ZNF74 into pGEX-KG for GST fusion
protein expression........................................ 59
附圖八、Constructions of different truncated and full length cDNA
fragment of ZNF74 into pcDNA-HA for mammalian cell expression…60
附圖九、Constructions of different truncated and full length cDNA
fragment of ZNF74 into p-MAL-c2x for MBP fusion
protein expressio……………………………………………………… 61
附圖十、Transient transfection of ZNF74 variants expressed in
HEK293 cell………………………………………………………………62
附圖十一、GST-ZNF74-3Z fusion protein expressed as inclusion body
after IPTG induction in E. coli BL-21…………………………… 63
附圖十二、GST-ZNF74-6Z fusion protein expressed as inclusion body
after IPTG induction in E. coli BL-21……………………………64
附圖十三、GST-ZNF74-9Z fusion protein expressed as inclusion body
after IPTG induction in E. coli BL-21……………………………65
附圖十四、GST-ZNF74-12Z fusion protein expressed as inclusion body
after IPTG induction in E. coli BL-21……………………………66
附圖十五、GST-ZNF74-full length fusion protein expressed as
inclusion body after IPTG induction in E. coli BL-21…………67
附圖十六、MBP-ZNF74 fusion proteins expressed in E. coli TB-1…………68
附圖十七、Identification of ZNF74-N1-rac associated complexs by coimmunoprecipitation with anti-Notch 1 C-terminal
antibody from cell extract of HEK293 cell constitutively expressing N1-rac…………………………………………………… 69
附圖十八、Identification of ZNF74-N1-rac associated complex by coimmunoprecipitation with anti-HA antibody from cell
extracts of HEK293 constitutively expressing N1-rac…………70
附圖十九、MBP fusion protein pull down assay to prove the
association of ZNF74 with N1-rac…………………………………71
附圖二十、Comparison of the functional regions of zinc finger
proteins in this study by alignment analysis…………………73
附圖二十一、PCR amplification of SELEX………………………………………74

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