在過去幾十年的研究中，人體醣類代謝的研究是一個重要的課題。在1990年woodgett等人的研究中發現了一種蛋白質，它是絲胺酸及酥胺酸激酶 (serine/threonine kinase)，並發現此蛋白質從酵母菌到哺乳動物細胞都參與了醣類代謝的角色，此蛋白質叫作肝醣合成激酶3b(Glycogen synthase kinase 3b簡稱GSK3b)。當初命名為GSK-3b原因是在哺乳動物細胞中，它能將肝醣合成酶(glycogen synthase簡稱GS)磷酸化，進一步調節肝醣的合成。
近這五年來許多的文獻研究報告指出，GSK3b也可以調節哺乳動物轉錄因子的活性，使得這些轉錄蛋白影響到其下游基因是否能表現。在某些生物體中，GSK3b也會影響到個體內基因訊息傳遞，引導細胞走向死亡或存活的途徑或者個體的發育。所以GSK3b在生命體中是一個很重要的一個蛋白質。
正因如此，我們實驗室想進一步找出在生命體中GSK-3b除了上面所言之外，是否還扮演了其他重要的角色。利用酵母菌雜交系統(yeast two-hybrid system)的方法以GSK3b為釣餌(bait)，來找尋與GSK3b交互作用的蛋白質。實驗上初步的結果來看，藉由此系統我們找到了二個新的蛋白質，一個為Human dynamin-like protein (HdynIV)，另一個為Human Ninein protein (hNinein)。
(一) 人類dynamin-like蛋白(Human dynamin-like protein)是一個 GTP結合蛋白(binding protein)，並屬於dynamin家族的成員之一。Dynamin因會與微小管(microtubule)結合，一開始是被歸類為微小管結合蛋白(microtubule-binding protein)。後來發現，當細胞進行胞飲作用的時候，dynamin可以將細胞膜上所形成的液泡(vesicle)由細胞膜上包飲到細胞質內，以幫助細胞運送外來的蛋白質或將外來的微生物送到溶小體(lysosome)分解。文獻上指出Dynamin可分為三類，分別是Dynamin I、 Dynamin II及Dynamin III。我們找到的人類dynamin-like蛋白與前發現的不同，則把它歸類為第四類，所以稱為HdynIV。 HdynIV全長有699個胺基酸，此蛋白質的C端能和GSK-3b作用。從北方墨點法及isoform specific PCR的結果來看，HdynIV表現在所有的人類組織中。
為了近一步探討此基因是否普遍存在哺乳動物中，我們以齧齒類的動物老鼠腦的cDNA library為材料，利用PCR的方法放大dynamin-like此基因。我們發現在老鼠中可以找到至少3種老鼠dynamin-like蛋白 (簡稱DLP1)，並且其中一種蛋白是文獻上所沒有報導過的。最長的DLP1有718個胺基酸。我們利用酵母菌雜交系統進一步證實這3種蛋白質都可以與GSK-3b作用。由北方墨點法的結果看來，此3種蛋白質在老鼠的組織中都有表現，並且在in vitro kinase的實驗中我們更進一步證明DLP1是GSK-3b的受質之一。在病理學上，我們萃取人類腦瘤組織的total RNA，利用RT-PCR的方法找到在人類組織中至少有4種dynamin-like蛋白 (HdynIV)，它們分別是HdynIV-WT、HdynIV-11、HdynIV-26及HdynIV-37。其中HdynIV-26在人類腦腫瘤組織中有大量表現的現象。我們推測HdynIV-26可能與腦腫瘤的形成有關係。
(二)另一個GSK3b的受質蛋白質是人類 Ninein (Human Ninein)。Ninein全長有2096個胺基酸。以一級結構而言，此蛋白質的N端有3個GTPase domain，中間及C端共有4個leucine zippers。以二級結構而言，此蛋白擁有許多的coiled-coil domain。利用酵母菌雜交系統我們證實了Ninein的C端能和GSK-3b作用。從北方墨點法及isoform specific PCR的結果來看，Ninein在所有的人類組織中都有表現。將Ninein構築在GFP之後，並送入細胞中發現，此蛋白質位在細胞的中心體(centrosome)上。利用免疫螢光染色的方法我們亦證實，將細胞停留在mitosis時，Ninein此蛋白質在metaphase及anaphase有消失的情形。在in vitro及in vivo的結果也證明人類Ninein本身會自我結合。在自體免疫的病人如SLE、DA及RA病人的血清中也可偵測到此蛋白質的存在。在genome的分析上我們發現，Ninein位在14q22上，此基因含有29個exons 28個introns。另外從genome上也可發現另一個異構物(isoform)的存在。而此基因的promotor含內有一個TATA box，二個CCAAT，三個GC box以及轉錄因子結合位如Sp1, p300及AP1等。
綜合以上，我們新發現的二種新蛋白質HdynIV或是hNinein可能參與GSK-3b在細胞訊息傳遞以及功能的調節上扮演密切關係的角色。

Over the past decade, the study of glycogen metabolism was an important subject in human. In 1990, Woodgett et, al. found that a serine-threonine kinase first characterized for its role in glycogen metabolism has shown itself to be a key player in numerous processes, in organisms ranging from yeast to mammals. The protein was Glycogen synthase kinase-3(GSK-3b). GSK-3b was first discovered by virtue of its ability to phosphorylate glycogen synthase and regulatory enzyme of glycogen synthesis in mammals.
Recently, GSK-3b have been identified that can modulate transcriptional factors and effect their functions. It has also been implicated in the regulation of cell fate in animals. On the other words, GSK3b is very important factor in mammalian cells. Using human GSK-3b as a bait and human fetal liver cDNA library as a prey in the yeast two-hybrid system, we identified two novel human GSK-3b interaction proteins. One is human dynamin-like protein (HdynIV) and the other is human ninein protein. (hNinein).
Human dynamin-like protein is a large GTP-binding protein. It is a member of dynamin family. Dynamin was initially identified as a microtubule-binding protein. When cells process endocytosis, dynamin can pitch the vesicle from cell membrane to cytosol. Dynamin also can help transportation of protein and take microbiology into lysosome. Perviously studies, dynamin could be classified three forms. There were Dynamin I、Dynamin II and Dynamin III. The human dynamin-like protein that we found is designated HdynIV. The full length cDNA of HdynIV has 699 amino acids. Its C-terminal of HdynIV can interact with GSK-3b using yeast two-hybrid system. By Northern blot and isoform specific PCR, we found that HdynIV is ubiquitously expressed in all human tissues. In pathology, we extracted total RNA of human brain tumor tissues, and we found at least four human dynamin-like isoforms by RT-PCR. There were human dynamin-like-wild type (HdynIV-WT), human dynamin-like-11(HdynIV-11), human dynamin-like-26 (HdynIV-26) and human dynamin-like-37 (HdynIV-37). Our data show that HdynIV-26 overexpressed in human brain tumor tissues. We suggested that HdynIV-26 may play a role in brain tumorigenesis.
On the other way, we identified that three forms of rat dynamin-like protein (DLP1) in rat brain cDNA library. One of these forms is a novel gene that is not be reported yet. We examined the interaction of these three rat brain DLP1 with GSK3b using the yeast two-hybrid. By Northern blot, we found that rat DLP1is expressed ubiquitously in all tissues. In vitro kinase assay data showed that DLP1 acts as a substrate of GSK3b.
Another candidate of GSK3b is human Ninein (hNinein). The full length cDNA of hNinein encoded a protein consisting 2096 amino acids. The features of this protein include a potential GTP binding site,in its N-terminal, a large coiled-coil domain together with four leucine zipper domains. Using the yeast two-hybrid, we identify the C terminal of hNinein that can interact with GSK3b. Our results also demonstrate that GSK3b can co-localize with human ninein in HeLa cells. By Northern blot and isoform specific PCR, hNinein is ubiquitously expressed in all human tissues. When we transfected GFP-hNinein into HeLa cells, we found that hNinein is localized in the centrosome. In cell cycle experiments Ninein was diminish in metaphase and anaphase, but reaccumulated in telophase.. In pathology, hNinein also was showed to react with autoantibody sera. The Ninein genome was found to correspond to 29 exons and 28 introns of genomic sequence on human chromosome 14q22. In addition, an alternatively splicing form can be found from genome sequence. Promoter analysis predicts that hNinein contains a TATA, two CCAAT, and three GC box. The promoter also exhibits the following potential transcription factor binding sites including Sp1, p300 and AP-1.
In conclusion, we suggesting that HdynIV and hNinein proteins may play an important role in anchoring of GSK3b to ER and mitochoria or centrosome for signal transduction and metabolic regulation.

頁次
壹：中文摘要………………………………………………………........1
貳：英文摘要……………………………………………………………5
參：縮寫表………………………………………………………………8
肆：試劑組與藥品名稱………………………………………………..10
伍：第一章 緒論………………………………………………………12
陸：第二章Human dynamin-like protein interacts with
glycogen synthase kinase 3b…………………………...... 24
序言……………………………………………………………….. 25
(a) 實驗方法與步驟…………………………………………………... 27
(b) 結果與討論……………………………………………………….. 44
(c) 圖表……………………………………………………………… 49
柒：第三章Three rat brain alternative splicing dynamin-like
protein variants: interaction with the glycogen
synthase kinase 3b and action as a substract……………..60
序言………………………………………………………………..61
(a) 實驗方法與步驟…………………………………………………... 63
(b) 結果與討論…………………………………………………………73
(c) 圖表…………………………………………………………………77
捌：第四章Differential expression of four human dynamin-like
protein variants in brain tumor…………………………...85
序言…………………………………………………………………. 86
(a) 實驗方法與步驟……………………………………………………87
(b) 結果與討論…………………………………………………………90
(c) 圖表…………………………………………………………………93
玖：第五章Cloning and characterization of a novel human
ninein protein that interacts with the glycogen
synthase kinase 3b……………………………………….99
序言………………………………………………………………100
(a) 實驗方法與步驟…………………………………………………. 102
(b) 結果與討論……………………………………………………….116
(c) 圖表……………………………………………………………….125
拾：第六章 Genomic organization and molecular characterization
of human ninein gene………………………………… ..150
序言……………………………………………………………....151
(a) 實驗方法與步驟………………………………………………….152
(b) 結果與討論……………………………………………………….155
(c) 圖表…………………………………………………………….....159
拾壹：第七章 總結論…………………………………………….....168
拾貳：附錄一 論文與學會發表…………………………………….181
附錄二 主要論文著作……………………………………….185
拾參：參考文獻

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