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研究生:賴威仲
研究生(外文):Wei-Chung Lai
論文名稱:白色念珠菌C D C 4 結構域功能的解析
論文名稱(外文):Dissecting the domain function of Candidaalbicans SCFCDC4
指導教授:謝家慶
指導教授(外文):Jia-Ching Shieh
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:生物醫學科學學系碩士班
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:2008
畢業學年度:96
語文別:英文
論文頁數:74
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白色念珠菌 (Candida albicans) 是一種主要的伺機性真菌病源,尤其是對於免疫低落的病患造成生命威脅。多形性的細胞形態使白色念珠菌得以適應不同的環境並深植於寄主身上不同的組織。白色念珠菌的形態轉換與細胞週期有密切關聯。在泛素化調控的細胞週期中,SCF複合體扮演著一個重要的調節者。在泛素化過程中,SCF複合體作為E3泛素連接酶。這類連接酶主要由Skp1p、Cul1p以及F-box蛋白質所組成。其中,Skp1p與Cul1p是這類SCF複合體的共有元件,而F-box蛋白質則為一個辨識受質的多樣性元件,像是Cdc4p。在出芽酵母菌 (Saccharomyces cerevisiae) 中,SCFCdc4p在調節細胞週期G1到S時期特定蛋白質的泛素化過程作為一個關鍵的角色。由於出芽酵母菌的CDC4 (ScCDC4) 突變會造成細胞週期停滯於G1到S時期,因此ScCDC4基因是一個必要基因。藉由恢復出芽酵母菌cdc4-3溫度敏感突變株,我們得到白色念珠菌的CDC4同源基因 (CaCDC4)。然而,當CaCDC4沒有表現時,白色念珠菌會由酵母菌形態轉變為菌絲形態,意指CaCDC4是菌絲生長的負調節者,而對細胞週期所帶來的影響仍未明瞭。我們對於CaCDC4與ScCDC4之間出現如此戲劇化的功能轉變感到興趣,因而想要了解CaCdc4p的結構域功能對於形態轉變的關係。將CaCdc4p分為不同的結構域以四環黴素基因調控系統 (Tet-on system) 來進行功能解析。所使用的這款四環黴素調控系統為一個經改造且具廣泛使用性的系統。由四環黴素結構類似物多西環素 (Doxycycline) 誘導的各式CaCdc4p結構域的表現顯示CaCdc4p本身的不穩定特性,意指對於CaCdc4p的穩定性調節可能在功能上是重要的。同時以多西環素誘導各式的CaCdc4p表現並以甲硫氨酸及半胱氨酸調節CaMET3 啟動子抑制CaCDC4在菌株JSCA0021及其衍生菌株,藉由顯微鏡及解剖顯微鏡觀察細胞和菌落的型態改變,獲得不同的型態結果。與Skp1p相互作用的F-box domain,以及負責辨識受質的WD40 repeats,似乎具有Cdc4p功能的決定性,不論這兩者是否受到多西環素誘導表現,其結果皆如同CaMET3啟動子抑制CaCDC4所表現的菌絲形態。令人感興趣的是,即便多西環素誘導CaCdc4p表現卻無法阻止由CaMET3啟動子抑制CaCDC4所造成的菌絲生長,反而是減弱了細胞聚集 (flocculation) 的現象。因此,我們推測可能CaMET3啟動子會迅速地抑制CaCDC4而多西環素不及誘導CaCdc4p,所導致的菌絲形態無法回復成酵母菌形態。此外,根據缺少CaCDC4的細胞增強細胞聚集的能力,而聚集現象並不一定會伴隨菌絲生長,因此推測CaCDC4具有一個新功能為黏附現象 (adhesion) 的負調節。關於優化型態分析的條件以及針對型態定量分析的發展將會更適於定義CaCdc4p的結構域功能。

Candida albicans has been known to be a major opportunistic fungal pathogen in human, especially threatening life of immunocompromised patients. The polymorphic cell type allows C. albicans to adapt to different environmental conditions and to colonize different tissues in hosts. Morphological transition of C. albicans is closely associated with cell cycle. SCF complexes are key regulators via ubiquitin-proteasome system in cell cycle control. The SCF complexes function as E3 ubiquitin ligase and consist of common components Skp1p, Cul1p and a variable component of F-box protein such as Cdc4p for substrate recognition. SCFCdc4p plays an important role for ubiquitination of specific target proteins to enter S phase from G1 in Saccharomyces cerevisiae. S. cerevisiae CDC4 (ScCDC4) is an essential gene, mutation of which gives rise to cell cycle arrest at G1/S transition. We have identified a homologue of ScCDC4 in C. albicans (CaCDC4) by its ability to rescue the temperature sensitivity of S. cerevisiae cdc4-3 mutant. However, C. albicans grows as filaments in the absence of CaCDC4, suggesting that CaCdc4p serve as negative regulation of filamentation and its influence about cell cycle is unknown. I have been interested in understanding the dramatic functional change between CaCDC4 and ScCDC4. Accordingly, to determine the domain function of CaCdc4p for morphogenesis, I have carried out dissecting the function of CaCdc4p domains in C. albicans with the Tet-on system, the pTET25M and its derivatives, which I have made improvement from the original pTET25 for broader application. Under the Tet-on system, the doxycycline-inducible expression of assorted CaCdc4p domains detected by Western blotting revealed the instability nature of CaCdc4p due to its cleavage at N-terminal region and weak signal of full-length CaCdc4p, suggesting that regulation of stability of CaCdc4p may be important for its function. By expressing each of assorted CaCdc4p domains under the Tet-on system in a C. albicans strain with one CaCDC4 allele deleted and the other under control of CaMET3 promoter simultaneously, JSCA0021 and its derivatives, the phenotypic consequences containing morphological alteration of cell form in the liquid medium and colonies on the agar solely from each of those domains were assessed under microscope and stereo microscope. It appeared that domains of F-box and WD40 repeats, known to responsible for interaction with Skp1p of SCF complex and substrate specificity, respectively, were critical for the function of CaCdc4p, because phenotypes in strains with or without expression of each of these two domains under the CaMET3 promoter repressed condition were the same into filamentous growth and cell aggregation (flocculation). Interestingly, the doxycycline-induced full-length CaCdc4p decreased cell aggregation (flocculation) rather than suppressed filamentous development in the strain where another CaCDC4 being simultaneously repressed by CaMET3 promoter. As a result, I suggested that perhaps time required for the CaMET3 promoter repression is swift than that for the Tet-on induction and that irreversibility of cells from filament to yeast in C. albicans. In addition, I suggested a novel function of CaCDC4 for negatively regulating adhesion as cells lacking CaCDC4 increase the ability of flocculation, which is normally not associated with filamentation. Optimization of the phenotypic analysis and development of quantitative assays are thus crucial to adequately examine the domain function of CaCdc4p.

摘要 --------------------------------------------------------------------------------------- 1
Abstract ------------------------------------------------------------------------------------ 3
1. Introduction
1.1 Candida albicans and human disease----------------------------------------- 5
1.2 The nature of C. albicans------------------------------------------------------- 6
1.3 Molecular genetic tools--------------------------------------------------------- 8
1.4 Role of CaCDC4 in C. albicans ---------------------------------------------- 12
1.5 The goal of this study----------------------------------------------------------- 14
2. Materials and Methods
2.1 Strains and growth conditions------------------------------------------------- 16
2.2 Plasmid constructions---------------------------------------------------------- 17
2.3 Site directed mutagenesis------------------------------------------------------ 20
2.4 C. albicans transformation----------------------------------------------------- 20
2.5 Yeast colony PCR--------------------------------------------------------------- 21
2.6 Protein extraction and Western blotting-------------------------------------- 22
3. Results
3.1 Modification of a tetracycline-inducible gene expression system with
mini Ura blaster-------------------------------------------------------------------- 25
3.2 Construction of a series of pTET25M plasmids capable of expressing
assorted domains of CaCdc4p --------------------------------------------------- 26
3.3 Construction of a C. albicans strain capable of conditionally expressing
CaCDC4---------------------------------------------------------------------------- 29
3.4 Construction of a series of C. albicans strains capable of expression
assorted CaCDC4 domains induced by doxycycline-------------------------- 31
3.5 Analysis of aggregation of strains expressing a variety of CaCdc4p
domains----------------------------------------------------------------------------- 33
3.6 Invasive assay of strains expressing a variety of CaCdc4p domains---- 34
4. Conclusion and Discussion-------------------------------------------------------- 36
5. Tables
Table 1 Strains used in this study------------------------------------------------- 43
Table 2 Primer sequences used in this study------------------------------------- 44
6. Figures
Figure 1 Modification of a tetracycline-inducible gene expression system with mini Ura-blaster
(A) Reconstitution of mini Ura blaster------------------------------------------- 45
(B) Constitution of vector pTET25 with its GFP replaceable---------------- 46
(C) Restriction diagnosis of pTET25M and intermediate vectors----------- 47
(D) Improvement of pTET25M with more restriction enzyme sites--------- 48
Figure 2 Construction of a series of pTET25M plasmids capable of expressing assorted domains of CaCdc4p
(A) Construction of pTET25M-CaCDC4 and pTET25M-CaCDC4-6HF-- 49
(B) Construction of plasmids capable of expressing assorted CaCdc4p domains under the Tet-on system-------------------------------------------- 50
(C) Construction of plasmids capable of expressing CaCDC4 fused with GFP at N- and C-terminus of CaCdc4p------------------------------------ 51
(D) Analysis of restriction digestion on plasmid constructions for Tet-on system--------------------------------------------------------------------------- 52
Figure 3 Construction of a C. albicans strain capable of conditionally expressing CaCDC4
(A) Deletion of the first CaCDC4 allele with PCR amplicons of mini Ura Blaster------53
(B) Generation of the second CaCDC4 allele under conditional regulation of CaMET3 promoter-------------------------------------------------------------- 54
(C) The removal of CaURA3 selectable marker by 5-FOA ------------------- 55
(D) Strain constructions confirmed by yeast colony PCR --------------------- 56
(E) Morphological alteration arisen from depletion of CaCdc4p under CaMET3 repressed condition with or without CaURA3 ------------------ 57
Figure 4 Construction of a series of C. albicans strains capable of expression assorted CaCDC4 domains induced by doxycycline
(A) Integration of linearized pTET25M into C. albicans---------------------- 58
(B) Verification of Tet-on cassettes being integrated into CaADH1 locus by yeast colony PCR--------------------------------------------------------------- 59
(C) Western blotting analysis used to reveal the expression of assorted CaCdc4p domains inducing by doxycycline-------------------------------- 60
Figure 5 Phenotypic analysis of strains capable of expressing assorted CaCdc4p domains in liquid medium
(A) Cell maintenance in the suspension------------------------------------------ 61
(B) Microscopic analysis----------------------------------------------------------- 62
(C) Cell aggregation in the cuvette ----------------------------------------------- 63
(D) Comparison of level of cell aggregation------------------------------------- 64
Figure 6 Invasive assay of strains capable of expressing assorted CaCdc4p domains
(A) Colony morphology------------------------------------------------------------ 65
(B) Invasion in the agar ------------------------------------------------------------ 66
7. References---------------------------------------------------------------------------- 67


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