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研究生:黃勝彥
研究生(外文):Sheng-Yen Huang
論文名稱:鎘干擾G1到S期細胞週期運轉之探討
論文名稱(外文):Investigation of the progression of G1 phase to S phase interfered by cadmium chloride
指導教授:楊嘉鈴
指導教授(外文):Jia-Ling Yang
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:64
中文關鍵詞:細胞週期
外文關鍵詞:G1 phaseS phaseCdcadmiumcell cycle
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鎘是環境中廣泛存在的重金屬致癌物質。細胞週期運轉機制的失控是造成癌症發生的重要原因之一。先前研究發現鎘會造成細胞停滯在有絲分裂期,以及降低S期細胞DNA複製。然而,鎘影響G1細胞週期運轉的分子機制仍然不清楚。在本論文中,我們利用人類肺癌細胞株CL3來研究鎘對於G1期細胞進入S時期的影響,並進一步探討其中分子層次的改變。利用aphidicolin將細胞同步化在G1/S臨界期,再處理40 mM氯化鎘2小時後(約七成細胞存活劑量),明顯地使細胞延遲進入S期。以相同劑量的鎘處理經由nocodazole釋放或逆流離心細胞分離系統所分離出的G1細胞,也同樣延遲G1細胞週期運轉。進而利用西方墨點法及免疫沉澱激酶活性分析法,研究鎘如何干擾由逆流離心細胞分離系統所分離出的G1細胞中調控細胞週期運轉的分子,結果顯示鎘明顯地延遲G1細胞中RB的磷酸化,降低Cdk4蛋白的含量及cyclin D1、cyclin E複合激酶的活性,但並不改變cyclin D1蛋白的含量。再者,鎘明顯地延遲調控S期運轉之cyclin A蛋白的表現及其複合激酶活性的活化,但並不影響Cdk2蛋白的含量。此外,在G1細胞中鎘也會誘發p38 MAPK激酶活性及p21WAP1蛋白的表現,但不誘發p53 (Ser15)磷酸化。p38 MAPK抑制劑SB202190會使未處理及鎘處理之G1細胞更為延遲進入S期,並且誘發p53 (Ser15)磷酸化,但卻降低細胞中p21WAP1蛋白的表現。綜合上述,鎘可能藉由降低Cdk4蛋白的含量及cyclin D1、cyclin E複合激酶的活性來延遲RB的磷酸化、進而降低cyclin A蛋白的表現及cyclin A等複合激脢活性的活化,因此延緩細胞進入S期。另外,G1細胞中活化的p38 MAPK可能降低p53 (Ser15) 磷酸化,使受損傷的細胞逃脫G1監控點。

Cadmium (Cd) is a ubiquitous environmental heavy metal that has been classified as a human carcinogen. Deregulation of cell cycle progression is an important issue to cause cancer. Previous studies indicate that Cd causes mitotic arrest and decreases replicative DNA synthesis. However, the effect of Cd on molecules regulating G1 cell cycle progression remains unclear. In this thesis, we explore whether Cd affects G1 cells entering S phase at molecular levels using synchronized human non-small lung carcinoma cells, CL3. CdCl2 (40 mM, 2 h) markedly delayed S phase progression of synchronous cells at the G1/S border derived from aphidicolin procedure. Cd also delayed G1 progression of cells synchronized at G1 phase derived from either the nocodazole release procedure or the counterflow centrifugal cell elutriation system. Using western blotting and immunocomplex kinase activity analysis techniques, we have observed that Cd significantly delayed RB phosphorylation, down-regulated the protein levels of Cdk4, and decreased cyclin D1- and cyclin E-associated kinase activity in elutriated G1 cells; however, the protein levels of cyclin D1 did not altered. Furthermore, exposure these elutriated G1 cells to Cd also markedly delayed the induction of cyclin A expression, and cyclin A-associated kinase activity; however, the protein levels of Cdk2 were unchanged. On the other hand, Cd induced p38 MAPK phosphorylation and p21WAP1 protein levels, but not phospho-p53 (Ser15) in elutriated-G1 cells. SB202190, an inhibitor of p38 MAPK, delayed G1 progression of untreated or Cd-treated elutriated-G1 cells, elevated phospho-p53 (Ser15) while decreased p21WAP1 levels. Taken together, these results suggest that Cd delays RB phosphorylation by decrease Cdk4 protein levels, and cyclin D1- and cyclin E- associated kinase activities, thereby further slow-down the expression of cyclin A and cyclin A associated kinase kinase activity to delay G1 to S progression. Additionally, the activated-p38 MAPK may result in decreased phospho-p53 (Ser15), which may allow damaged cells bypass G1 checkpoint.

Contents
Abbreviations ....... .............. .4
中文摘要.......... ................5
Abstract .......... ................6
Introduction ........................ 7
Literature Review
1. The control of cell cycle in G1 and S phases....10
2. Mitogen-activated protein kinases (MAPKs)..... 13
3. The role of ERK and p38 MAPKs in regulating G1 progression ............... ..... .. .14
4. Cadmium (Cd)
4-1. Cd associated diseases .......... ...... 16
4-2. Genotoxicity of Cd ....... ........... 17
4-3. Cd and free radicals ..................18
4-4. Carcinogenicity of Cd .................19
4-5. Cd, signal transduction, and gene expression ......20
4-6. Cd and cell cycle ................... 21
Materials and Methods
1. Materials ......... ...............22
2. Cell culture .......................22
3. Cell synchronization ...................22
4. Cd treatment .......................23
5. Flow cytometry analysis ................. 23
6. Whole cell extract (WCE) preparation and western blot analysis .......................... 24
7. Immunoprecipitation and cyclin-associated kinase assay.. 25
Results .......................... 26
Summary ......................... 27
Discussion .........................32
References .........................34
Figures ........................ 53

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