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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34693完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張智芬(Zee-Fen Chang) | |
| dc.contributor.author | Hsiao-Hui Lee | en |
| dc.contributor.author | 李曉暉 | zh_TW |
| dc.date.accessioned | 2021-06-13T06:23:01Z | - |
| dc.date.available | 2007-02-08 | |
| dc.date.copyright | 2006-02-08 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-01-24 | |
| dc.identifier.citation | 1. Coleman M.L. andOlson M.F. Rho GTPase signalling pathways in the morphological changes associated with apoptosis. Cell Death Differ 9: 493-504, 2002.
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Mol Cell Biol 20: 1526-1536, 2000. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34693 | - |
| dc.description.abstract | 在本實驗室過去的研究中發現Rho-associated kinase (ROCK)在phorbol-12-myristate-13-acetate (PMA)誘發D2骨髓血球細胞凋亡的過程中扮演決定性的角色。為了瞭解在這個過程中有哪些分子受到ROCK的調控而改變，我利用蛋白質體學的研究方法，發現heterogeneous nuclear ribonucleoprotein C1 and C2 (hnRNP C1/C2)這兩個pre-mRNA結合蛋白質在PMA誘發的凋亡前期細胞中，從細胞核位移到細胞質；這個hnRNP C1/C2位移現象並不是因為該細胞的核膜破損所造成，也無關於caspase的作用；而是透過ROCK調控的細胞骨架改變所引發的核轉出。在TNF-alpha所誘發NIH3T3凋亡細胞中也可觀察到這個現象。我在HEK293T細胞中過度表現活化態的ROCK就足以造成hnRNP C1/C2的核轉出；同時也證實hnRNP C1/C2的C端40個氨機酸序列是一個可受到ROCK調控的核轉出訊號。此外，我發現ROCK所造成的細胞骨架改變也影響了細胞核中RNA的生合成速率。這些結果指出在PMA誘發的凋亡細胞中，透過ROCK活化所產生的訊息會傳遞到細胞核，造成hnRNP C1/C2的核轉出、核結構改變以及整體性的基因表現降低。
由於促進細胞附著(adhesion)可以阻斷PMA誘發的細胞凋亡，說明細胞剝離(de-adhesion)作用在PMA誘發的細胞凋亡扮演重要角色。我發現當懸浮的D2細胞附著於fibronectin (FN)基質上時，其RhoA的活性會明顯地降低。利用具有能通透細胞膜的活化態TAT-RhoAV14重組蛋白質處理已附著於FN基質的細胞，透過ROCK的作用，伴隨著MLC磷酸化增加及細胞膜表面lipid rafts的重新分佈，D2細胞從FN基質剝離而呈現懸浮狀態。有趣的是這個現象可以藉由抑制protein tyrosine phosphatase (PTP)的活性，或表現抑制型態的Shp-2(C/S)所干擾。利用ROCK kinase活性的測定，我證實表現抑制型態的Shp-2(C/S)會抑制ROCK的活性；進一步發現若將ROCK的Serine 1134及1137位置突變成alanine時，則失去其被Shp-2(C/S)調控的特性。由於Shp-2基因在血液細胞生成的過程中是必須的，從我的研究中推測Shp-2可能在該過程中藉由影響RhoA/ROCK所調控的細胞附著機制而扮演重要角色。 | zh_TW |
| dc.description.abstract | In D2 cells, a myeloid leukemia cell line, Rho-associated kinase (ROCK) is required for phorbol-12-myristate-13- acetate (PMA)-induced apoptosis. Using a proteomic approach, I found that heterogeneous nuclear ribonucleoprotein C1 and C2 (hnRNP C1/C2), two nuclear restricted pre-mRNA binding proteins, are translocated to the cytoplasm in a ROCK-dependent manner in PMA-induced pro-apoptotic cells, where nuclear envelopes remain intact. The subcellular localization change of hnRNP C1/C2 appears to be dependent on ROCK-mediated cytoskeletal change and independent of caspase execution and new protein synthesis. This phenomenon is also observed in TNFalpha-induced apoptotic NIH3T3 cells. Over-expression of dominant active form of ROCK is sufficient to induce translocation of hnRNP C1/C2 in HEK293T cells. I also defined that C-terminal 40-amino-acid region of hnRNP C1/C2 is a novel nuclear export signal responsive to ROCK-activation. Besides, I found that ROCK-mediated cell contraction also induces down-regulation of general RNA synthesis. Here I conclude that a novel nuclear export is activated by the ROCK signaling pathway to exclude hnRNP C1/C2 from nucleus, by which the compartmentalization of specific hnRNP components is disturbed in apoptotic cells.
Since PMA-induced apoptosis could be inhibited by cell adhesion, here I also investigated regulation of ROCK signaling in cell adhesion. The results showed that the RhoA activity was down-regulated while D2 cells were adherent to fibronectin (FN) matrix. Treatment of cell-permeable dominant active form of TAT-RhoAV14 induces cell de-adhesion from FN matrix, accompanying by lipid rafts redistribution and myosin light chain (MLC) phosphorylation. Interestingly, inhibition of tyrosine phosphatase or co-expression of catalytically inactive tyrosine phosphatase Shp-2(C/S) abrogated the RhoAV14-induced cell de-adhesion. By in vitro kinase analysis, I demonstrated that ROCK kinase activity was repressed in the cells co-expressing dominant negative Shp-2(C/S). Interestingly, mutation on S1134A/S1137A of ROCK abrogated its Shp-2(C/S)-responsive down-regulation. Given that the gene targeted mice experiment has shown that Shp-2 gene is essential for hematopoiesis. The results of my study suggest that Shp-2 may play a pivotal role in the myelopoiesis through regulating RhoA/ROCK-mediated cell de-adhesion. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T06:23:01Z (GMT). No. of bitstreams: 1 ntu-95-D89442006-1.pdf: 3607870 bytes, checksum: 334fcc7a89ef5b95ad8754a0b0b86887 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | 中文摘要 ………………………………………………………… I
Abstract ………………………………………………………… II Content …………………………………………………………… III Preface …………………………………………………………… 1 Chapter I. Overview of Rho-associated kinase Introduction …………………………………………………… 2 I-1. Structure of Rho-associated kinase ………………… 3 I-2. The functions of ROCK in cells: substrates for phosphorylation ………………………………………………… 5 I-3. The regulation of Rho-associated kinase. ………… 9 Chapter II. Nuclear efflux of heterogeneous nuclear ribonucleoprotein C1/C2 in apoptotic cells: a novel nuclear export dependent on Rho-associated kinase activation Introduction……………………………………………………… 14 Materials and Methods ………………………………………… 17 Results …………………………………………………………… 22 Discussion………………………………………………………… 30 Figures and Legends…………………………………………… 34 Chapter II. Regulation of RhoA/ROCK-mediated cell detachment: the involvement of Shp-2 Introduction……………………………………………………… 48 Materials and Methods ………………………………………… 50 Results …………………………………………………………… 53 Discussion………………………………………………………… 57 Figures and Legends…………………………………………… 60 References ……………………………………………………… 71 Appendix Table 1. The Substrates of Shp-2 ………………………… 81 Table 2. The Substrates of Shp-1 ………………………… 82 Table 3. The interacting proteins of Shp-2 …………… 83 Table 4. The interacting proteins of Shp-1 …………… 85 | |
| dc.language.iso | en | |
| dc.subject | phorbol ester | zh_TW |
| dc.subject | Rho-associated kinase | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | phorbol ester | en |
| dc.subject | Rho-associated kinase | en |
| dc.subject | apoptosis | en |
| dc.title | Rho-associated kinase在phorbol ester誘發細胞凋亡之角色探討 | zh_TW |
| dc.title | Rho-associated kinase in phorbol ester-induced apoptosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 周祖述(Tzuu-Shuh Jou),陳鴻震(Hong-Chen Chen),陳玉如(Yu-Ju Chen),孟子青(Tzu-Ching Meng) | |
| dc.subject.keyword | Rho-associated kinase,phorbol ester,細胞凋亡, | zh_TW |
| dc.subject.keyword | Rho-associated kinase,phorbol ester,apoptosis, | en |
| dc.relation.page | 86 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-01-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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