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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華(Rhey-Hwa Chen) | |
| dc.contributor.author | Yuan-Ping Huang | en |
| dc.contributor.author | 黃元平 | zh_TW |
| dc.date.accessioned | 2021-06-13T08:24:51Z | - |
| dc.date.available | 2005-08-02 | |
| dc.date.copyright | 2005-08-02 | |
| dc.date.issued | 2005 | |
| dc.date.submitted | 2005-07-15 | |
| dc.identifier.citation | Adinolfi, E., M. Kim, et al. (2003). 'Tyrosine phosphorylation of HSP90 within the P2X7 receptor complex negatively regulates P2X7 receptors.' Journal of Biological Chemistry 278(39): 37344-51.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/36958 | - |
| dc.description.abstract | 乳癌激酶(Breast tumor kinase, Brk)是屬於Src-like酪氨酸激酶家族中的一員，在大部分惡性乳癌細胞株中都有大量表現。先前的研究已證實乳癌激酶的表現與乳癌病灶的進程有很大的關係，然而乳癌激酶促進癌症發展的分子機制至今仍不是十分清楚。在本篇論文中，我們發現了Paxillin是乳癌激酶的一個新受質。在細胞內乳癌激酶的表現會促進Paxillin 的酪氨酸磷酸化，而且乳癌激酶和Paxillin在細胞內會彼此結合。此外，我們也證實了Paxillin的N端LD區域以及C端LIM區塊均可以直接和乳癌激酶相互作用。我們同時也發現了乳癌激酶會和Hsp90互相結合。以Geldanamycin抑制Hsp90的活性會造成乳癌激酶的泛素化(ubiquitination)增加，這個現象在我們使用乳癌激酶的永久活化突變型(BrkY447F)時更加明顯，表示活化的乳癌激酶會受到Hsp90的保護而免於受到 泛素化而降解。我們接著也證實了CHIP 可能是造成乳癌激酶在Hsp90被抑制下泛素化上升的ubiquitin ligase。另外，我們發現表皮生長激素(EGF)會經由活化一種ubiquitin ligase Cbl促進乳癌激酶的泛素化進而激化乳癌激酶的蛋白質降解。我們的實驗結果顯示乳癌激酶的訊息傳遞不僅受到Hsp90的保護，同時受到Cbl及CHIP造成之乳癌激酶泛素化的負向調控。 | zh_TW |
| dc.description.abstract | Breast tumor kinase (Brk) is a Src-like family non-receptor tyrosine kinase over-expressed in most breast cancer cells. Previous studies have established the correlation of Brk expression and the progression of malignancy. However, the exact biological function of Brk and the molecular mechanism through which Brk contributes to tumor metastasis remain to be elucidated. In this thesis, we have identified Paxillin as a novel cytosolic substrate of Brk. Expression of Brk significantly enhanced tyrosine phosphorylation of Paxillin, and these two proteins interacted with each other in vivo. We also showed that both N-terminal LD region and C-terminal LIM domain of Paxillin could mediate interaction with Brk. Besides, we found Hsp90 interacts with Brk in vivo. Subsequent experiments demonstrated that active Brk is under the protection of Hsp90 that its inactivation by treatment of geldanamycin (GA) results in ubiquitination of Brk mediated by the ubiquitin ligase C-terminus of Hsc70 interacting protein (CHIP). Moreover, we found that EGF treatment stimulated protein turnover of Brk through ubiquitination catalyzing by the ubiquitin ligase Cbl that is activated in response to EGF signal. These data suggested signaling of Brk is escorted by Hsp90 and negatively regulated by Cbl/CHIP-mediated ubiquitination. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T08:24:51Z (GMT). No. of bitstreams: 1 ntu-94-R92448006-1.pdf: 2726077 bytes, checksum: f8e19d62d112444278cda020ba87b699 (MD5) Previous issue date: 2005 | en |
| dc.description.tableofcontents | 中文摘要 3
Abstract 4 Introduction 5 Signal transduction in oncogensis 5 Malignancy: angiogenesis and metastasis 6 Src family kinases 7 Breast tumor kinase 9 Paxillin 11 Ubiquitination 12 Heat shock protein 90 13 Carboxyl terminus of Hsc 70 interacting protein (CHIP) 15 Casitas B lymphoma (Cbl) 16 Results 18 Identification of Paxillin as a substrate of Brk 18 Brk-induced Paxillin phosphorylation is independent of FAK 19 Brk interacts with Paxillin in vitro and in vivo 19 Activated Brk is predisposed to ubiquitination 21 Identification of Brk-interacting proteins 22 Hsp90 interacts with Brk in vivo 22 Inactivation of Hsp90 promotes ubiquitination of Brk 23 CHIP acts as an ubiquitin E3 ligase of Brk 24 EGF stimulation promotes ubiquitination of Brk 25 EGF signaling stimulates protein turnover of Brk 25 Cbl mediates ubiquitination of Brk following EGF signaling 26 Discussion 28 References 34 Figures 48 Figure 1. Activation of c-Src 48 Figure 2. Paxillin interactions 49 Figure 3. Domain structure of Cbl family ubiquitin ligase 50 Figure 4. Brk promotes tyrosine phosphorylation od Paxillin. 51 Figure 5. Brk does not influence tyrosine phosphorylation of FAK. 52 Figure 6. Brk and Paxillin interact reciprocally in vivo. 53 Figure 7. Both N-terminal and C-terminal fragments of Paxillin are capable of interacting with Brk in vitro. 54 Figure 8. Schematic model of the signaling pathway Brk participates in. 55 Figure 9. Brk Y447F is more susceptible to ubiquitination. 56 Figure 10. Characterization of Brk-interacting proteins 57 Figure 11. Brk interacts with Hsp90 in vivo. 58 Figure 12. Hsp90 interacts with Brk in vivo. 59 Figure 13. Inhibition of Hsp90 promotes ubiquitination of Brk. 60 Figure 14. CHIP interacts with Brk in vivo. 61 Figure 15. CHIP mediates ubiquitination of Brk. 62 Figure 16. Ubiquitination of Brk is enhanced flowed by EGF treatment in a time-dependent manner. 63 Figure 17. EGF treatment stimulates protein turnover of Brk. 64 Figure 18. Brk interacts with Cbl in vivo. 65 Figure 19. Cbl interacts with Brk in vivo. 66 Figure 20. Cbl is capable of catalyzing ubiquitinatiob of Brk. 67 Figure 21. Cbl S381A blocks the effect of EGF on ubiquitination of Brk. 68 Figure 22. Model of Brk regulation by Hsp90 and ubiquitination. 69 Material and methods 70 | |
| dc.language.iso | en | |
| dc.subject | 泛素化 | zh_TW |
| dc.subject | 訊息傳遞 | zh_TW |
| dc.subject | 乳癌激酶 | zh_TW |
| dc.subject | Ubiqitination | en |
| dc.subject | Brk | en |
| dc.subject | Hsp90 | en |
| dc.title | 乳癌激酶之訊息傳遞暨其受Hsp90與泛素化之調控 | zh_TW |
| dc.title | Signaling Transducation of Brk and Its Regulation by Hsp90 in Concert with Ubiquitination | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 93-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李芳仁,張智芬 | |
| dc.subject.keyword | 乳癌激酶,泛素化,訊息傳遞, | zh_TW |
| dc.subject.keyword | Brk,Hsp90,Ubiqitination, | en |
| dc.relation.page | 74 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2005-07-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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