臺灣博碩士論文加值系統

維他命A酸(RA)的生理作用被不斷地廣泛研究，包括在細胞與發育學、營養學、癌症治療等種種層面。過去研究發現，維他命A酸可以誘導人類血癌細胞進行細胞分化和生長停止，但是對於其中的分子機制還未完全清楚。核仁磷酸蛋白(B23)是細胞核內具有多功能的磷酸化蛋白，在不同情況下對於細胞生長、死亡、分化、中心體的複製、細胞週期的進行以及基因轉錄的調控等方面都有所參與。而當腫瘤細胞受到化學物質的刺激而進行細胞分化的情形下， B23是否擔當了關鍵的地位，這是個值得深入探索的問題。
過去我們實驗室的結果曾經觀察到，當人類急性前骨髓性血癌細胞株(HL-60 cells)受到維他命A酸的誘導而進行細胞分化時，B23、 c-Myc和YY1的蛋白質量表現皆會被抑制。在本篇研究論文中，主要目的是想進一步探討B23受到維他命A酸抑制的詳細機制，和B23在細胞分化過程中所扮演的角色。
結果發現B23啟動子的活性必須依賴位於其上的YY1和c-Myc的結合位置，一旦這些結合位置突變後，B23啟動子就會失去活性。而維他命A酸透過先抑制YY1和c-Myc的蛋白質量，進而造成YY1與c-Myc對於B23啟動子上其結合位置的活性降低，最後導致B23的活性下降。此外也觀察到B23會與AP-2α形成一個具有轉錄調控功能的複合物，而此複合物能結合到某些受維他命A酸抑制的基因啟動子上的AP-2α結合位置，包括B23自己啟動子上的AP-2α結合位置，並且維他命A酸可以增強此結合的表現。這些證據顯示出B23在細胞分化的過程中可以藉由與特定轉錄因子的結合，來參與基因轉錄層面的調控。

The biological effects, involved in cell and developmental biology, nutrition, and cancer chemotherapy, of retinoic acid (RA) have been well studied. RA is already known as a potent inducer of leukemia cell differentiation and growth arrest, but its molecular mechanisms are not fully defined. Nucleophosmin/B23 is a multifunctional nucleolar phosphoprotein. It plays critical roles in the control of centrosome duplication, cell cycle progression, cell proliferation, cell apoptosis, cell differentiation, and transcriptional regulation. Whether B23 is a key molecule involved in regulating the susceptibility of tumor cells to chemotherapeutics of cell differentiation becomes an important question to be addressed.
Our previous experiments have shown that B23, c-Myc, and YY1 are down-regulated during RA-induced HL-60 cell differentiation. In this study, attempts were further to elucidate the detailed mechanism of RA-mediated repression of B23, and the role of B23 during RA-induced HL-60 cell differentiation.
The results exhibited that the B23 promoter activity depends on intact YY1 and dual c-Myc binding sites, and mutation of these binding sites can abolish the B23 promoter activity. RA inhibits the expression of B23 by down-regulation of YY1 and c-Myc activities during cell differentiation. Moreover, the regulatory complex is formed with AP-2α and B23 in HL-60 cells, and targeted to the AP-2α binding sites in the promoters of RA-responsive gene, including B23. The bindings of the complex containing AP-2α and B23 to the RA-repressed genes are enhanced by RA treatment. These evidences suggest that B23 can involve in the transcriptional regulation by associating with transcription factors.

Chapter I Introduction………………………………………………1
Nucleophosmin (B23)………………………………….…………...1
All-trans retinoic acid (RA)……………………….……………….4
Human acute promyelocytic leukemia HL-60 cell line………..….6
c-Myc…………………………………………..…………….........6
Yin Yang 1 (YY1)………………………………..……….…..….8
Activator protein 2 (AP-2)………………………………………...9
Objectives of this study………………………………………..….10
Chapter II Materials and Methods…………………………………....11
Reagents…………………………………………………..…….....11
Cell culture…………….…………………..…….………….….…11
Determination of cell growth…………………………………….11
Determination of cell differentiation…………………………..….12
Western blotting………………………………………………..….12
Co-immunoprecipitation…...…………………….……………..…13
Plasmid constructions…………………………………………..…14
Electroporation………………………………………………....…15
Luciferase and β-galactosidase activity assays………………..…..15
RNA isolation and Reverse transcription-PCR (RT-PCR)…..…...15
Identification of transcription factor binding sites……………..…17
Chromatin immunoprecipitation (ChIP) assay…………………....17
Statistical analysis...…………………………………………….…19
Chapter III Results…………………………………………………....20
Cell growth and differentiation in RA-treated HL-60 cells……….20
Comparison of c-Myc, YY1, and B23 protein levels in RA-treated
HL-60 cells…………..................................................................…20
B23 promoter transcriptional activity with mutation at YY1 and
c-Myc binding sites ....................................................................…21
Physical interaction of c-Myc and YY1 with the B23 promoter..23
Association of B23 protein with AP-2α in vivo………………….24
B23 involved in the transcriptional regulation by associating
with transcription factors……………....…………………….…….25
Chapter IV Discussion………………………………………...……….29
Chapter V References………………………………………………….33
Chapter VI Figures……………………………………..……………..43
Chapter VII Appendix………………………..………….……………62

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