臺灣博碩士論文加值系統

本研究主要利用人類急性淋巴癌細胞株HL-60分化的細胞模式來探討細胞分化過程基因的調控。首先致力於開發新的實驗流程並結合基因微陣列技術，進行篩選及探討TPA誘導HL-60細胞分化過程之迅早期所誘發的基因。簡單來說，細胞先經過Nocodazole將細胞週期同期化之後，並以cycloheximde前處理1小時，再用TPA(實驗組)或DMSO (對照組)處理。細胞週期同期化可以避免細胞週期相關的基因在篩選過程中造成干擾；而cycloheximde可以抑制在TPA處理的過程中合成新的蛋白質，因而避免活化TPA間接調控的基因，經過如此的前處理過程，從細胞所取得的RNA中迅早期所誘發的基因所佔的比重相對的增加。接著利用基因微陣列的方法解讀這些受TPA調控的基因，經過不同的篩選條件和real-time PCR的反覆驗證後，得到56個TPA迅早期誘發的基因。為了將來能建構血球細胞分化的基因調控網路，本研究偏重在一些負責調控基因表現的基因，並且這些基因還未曾被提到參與血球細胞分化。並進一步驗證其中3個基因(NFIL3、SnoN、JMJD3) 在一般細胞培養條件下，TPA確實會誘發這3個基因的表現，並且呈現和劑量及時間都有明顯的正相關之結果。TPA對於這3個基因的調控機制，經過不同蛋白質激酶抑制劑(protein kinase inhibitor)的試驗後，發現這3個基因的表現都會受到PKC和MEK/ERK訊息的調控。以上的實驗結果顯示，有別於以往的基因篩選的實驗，本研究提供一個有效率的實驗流程有助於篩選出直接受調控的基因。而在本研究新發現受TPA直接調控的基因很可能在HL-60細胞分化過程中也扮演著相關的角色。
因此接下來選定SnoN基因為對象，深入探討SnoN的功能對於HL-60細胞分化的影響。SnoN基因最早被定義為致癌基因，它的作用機制主要被歸因於SnoN經由抑制Smads活化下游基因轉錄作用，進而對於TGF的訊息傳遞產生負調控的現象。然而SnoN對於myeloid細胞分化的角色還沒被探討過。因此本研究用HL-60細胞分化的模式探討SnoN對於細胞分化的重要性。結果發現在3種不同分化誘導劑 (TPA、VD3、ATRA) 處理的早期， SnoN蛋白質表現量都有明顯增加，暗示這3種分化誘導劑可能透過共通的機制去調控SnoN基因的表現，例如活化ERK。在TPA和VD3處理的細胞內SnoN基因的蛋白質表現量隨著時間持續增加，然而在ATRA處理的細胞內SnoN所增加的表現量一直維持在一定的量，暗示TPA和VD3可能額外透過其他的機制去調控SnoN基因的表現，例如Smads。在HL-60細胞中持續表現SnoN的干擾核糖核酸後，在3種分化誘導劑 (TPA、VD3、ATRA)刺激之下，細胞分化的效果顯著的增加。因此SnoN的表現可能是在細胞分化的早期扮演抑制作用。此外，HL-60細胞同時用VD3 和 TGF處理，TGF顯著的增加VD3對細胞分化的作用，但是在SnoN表現被抑制的細胞內並沒有觀察到這種協同作用。根據本研究的結果顯示SnoN在HL-60細胞分化的早期可能是扮演抑制的角色，而這個作用很可能是透過SnoN對於TGF/Smads訊息的抑制作用。

Human promyeloid leukemia cell line (HL-60) is a good model to study cell differentiation. HL-60 cells can be induced to differentiate into monocytes/ macrophages or granulocytes. We have adopted a special experimental strategy to identify early responsive genes during 12-O-tetradecanoylphorbol-13-acetate (TPA) induced macrophage-like differentiation of HL-60 cells. This was performed in HL-60 cells which were synchronized by nocodazole and treated with TPA in the presence of a protein synthesis inhibitor, cycloheximide, to prevent activation of secondary targets, therefore increase the probability of detecting early gene transcripts in total RNA pool. The gene expression alternation was then analyzed by microarray. The selection criteria of candidate genes were adjusted by real-time PCR validation to increase its reliability. Finally, 56 genes were identified as early TPA-responsive genes by this multi-screening step approach. In order to figure out the transcriptional regulatory network in the future, I selective focused on the transcriptional regulators which are never reported to involve in myeloid differentiation. Among these genes, three candidate transcriptional regulators NFIL3, SnoN, and JMJD3 was shown to be dosage- and time- dependent increased with TPA treatment and was found to be directly regulated by TPA through PKC and MEK/ERK signaling pathway. These results revealed that this screening-method provides a useful and efficient approach to identify early TPA-responsive genes and these genes might involve in the regulation of TPA-induced differentiation program of HL-60 cells as primary regulators.
SnoN is originally to be identified as an oncogene and it is an important negative regulator of TGF signaling through Smad proteins. However the roles of SnoN in myeloid differentiation have not been defined. Thus, this study further characterized the roles of the candidate gene SnoN during differentiation of HL-60 cells. It is interesting to find that the induction of SnoN in HL-60 cells was not lineage specific. Either by TPA and VD3 treatment to induce monocyte/macrophage or by ATRA treatment to induce granulocyte can observe the upregualtion of SnoN. Upregulation of SnoN by all these differentiating agents at the early stage of differentiation might be through a common pathway, such as ERK signaling. Additionally, SnoN was sustained increased expression at the late stage of monocye/macrophage differentiation by TPA and VD3 treatment, and it might through Samds pathway. Expression the knockdown construct bearing the shRNA for SnoN in HL-60 cells exhibited an enhanced differentiation by all three differentiating agents at the early stage. SnoN might serve as a repressor of differentiation at early stage in HL-60 cells. Combined with VD3 and TGF treatment can synergistically increased differentiation of HL-60 cells, but did not in HLiSno cells. Loss of repressor SnoN can enhance VD3-induced differentiation might through TGF/Smads signaling pathway. These findings suggested that SnoN may act as a non-lineage-specific repressor at early stage of differentiation in HL-60 cell through repression of TGF/Smads signaling pathway in part.

Contents ------------------------------------------------------------------------------------------ I
Table Contents --------------------------------------------------------------------------------- III
Figure Contents ------------------------------------------------------------------------------- IV
中文摘要 -------------------------------------------------------------------------------------- VI
Abstract --------------------------------------------------------------------------------------- VIII
Overview ----------------------------------------------------------------------------------------- 1
Materials and Methods ------------------------------------------------------------------------- 8
Cell culture and induction of differentiation ----------------------------------------------- 8
Differentiation assays ------------------------------------------------------------------------- 8
RNA extraction and RT-PCR --------------------------------------------------------------- 10
Schema for isolating early TPA-responsive genes -------------------------------------- 10
Microarray analysis -------------------------------------------------------------------------- 11
Quantitative real-time PCR assay --------------------------------------------------------- 13
Plasmid constructs --------------------------------------------------------------------------- 13
Transfection and virus infection ----------------------------------------------------------- 15
Nuclear protein extraction ------------------------------------------------------------------ 15
Immunoprecipitation assay ----------------------------------------------------------------- 16
Western blotting analysis (Immuno-blotting) -------------------------------------------- 16
Antibodies for Western blotting analysis ------------------------------------------------- 17
Cell Cycle analysis -------------------------------------------------------------------------- 17
Statistical analysis --------------------------------------------------------------------------- 17
Part I. Identification of early-TPA responsive genes during HL-60 cell
differentiation -------------------------------------------------------------------------- 18
Introduction (I) ----------------------------------------------------------------------------- 19
Results (I) ----------------------------------------------------------------------------------- 21
Discussion (I) ------------------------------------------------------------------------------- 28
Part II. Functional characterization of SnoN during HL-60 cell differentiation ------ 31
Introduction (II) ---------------------------------------------------------------------------- 32
Results (II) ---------------------------------------------------------------------------------- 34
Discussion (II) ------------------------------------------------------------------------------ 43
Concluding Remarks ------------------------------------------------------------------------- 48
References -------------------------------------------------------------------------------------- 49
Tables ------------------------------------------------------------------------------------------- 63
Figures ------------------------------------------------------------------------------------------ 72
Appendix --------------------------------------------------------------------------------------- 95

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