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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37229
標題: | IKKα 小泛素化在乳癌細胞遷移中扮演的角色 The role of IKKα SUMOylation in breast cancer cell migration |
作者: | I-Lin Ho 何宜霖 |
指導教授: | 徐立中(Li-Chung Hsu) |
關鍵字: | IKKa,小泛素化,乳癌, SUMOylation,IKKa,breast cancer, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 癌症雄踞各大死因之首已有十數年之久,而癌症轉移更是造成百分之九十以上癌症死亡的主要因素。轉錄因子NF-κB 對於調控許多細胞反應佔有極重要的角色,然而,NF-κB也被證明參與於癌症的發生中。由IKKα,IKKβ與IKKγ共同組成的IKK複合體是調控NF-κB訊息傳遞路徑的主要調控者。近年來,有研究指出在前列腺癌與乳癌中, RANKL會刺激IKKα進入細胞核中並抑制一轉移抑制蛋白質Maspin,進而促使癌症轉移發生。儘管IKKα的細胞核定位訊號(Nuclear localization signal)已經被發現, IKKα入核的詳細分子機制仍舊不清楚。
在此份研究中,我們在人類乳癌細胞MCF-7中發現了一個調控IKKα入核的新分子機制。小泛素化(SUMOylation)是一種普遍的轉譯後化學性修飾,並參與在許多重要的細胞反應中,包含調控細胞質與細胞核之間的物質運輸。當乳癌細胞處於細胞脫離(cell detachment)或RANKL的刺激下時,我們觀察到IKKα進入細胞核並伴隨著小泛素化的發生。除此之外,我們也發現在RANKL的刺激下,IKKα會與一SUMO E3 ligase RanBP2交互作用,顯示RanBP2可能參與於IKKα的小泛素化。在IKKα小泛素化去除之後,IKKα進入細胞核的量減少,同時也抑制了乳癌細胞的遷移能力。總而言之,我們發現了IKKα入核需要小泛素化的修飾,並且去除掉小泛素化可以降低乳癌細胞的遷移能力。這樣的研究結果可望對乳癌發生提供一些新的觀點,並希望能應用於乳癌治療上。 Cancer is the major cause of death worldwide, and cancer metastasis is the critical factor with a poor prognosis resulting in a mortality rate of more than 90%. Transcription factor NF-κB is pivotal for many cellular responses, however, NF-κB has also been demonstrated to be involved in cancer development and progression. IKK complex, which is composed of IKKα, IKKβ and IKKγ, is the key regulator in NF-κB signaling pathway. Recently, IKKα has been reported to promote prostate cancer and breast cancer metastasis by activating its nuclear translocation leading to repress metastatic inhibitor, Maspin after RANKL engagement. Although the nuclear localization signal of IKKα has been already identified, the molecular mechanism of IKKα nuclear translocation still remains to be investigated. In this study, we unraveled a novel mechanism of IKKα nuclear translocation in human breast cancer cell MCF-7. Post-translational modifications confer many important cellular responses, including cytoplasmic-nuclear transport. Upon the stimulation of cell detachment and RANKL engagement, we observed IKKα nuclear translocation, which is accompanied with a post-translational modification. The abolishment of the post-translational modification can inhibit IKKα nuclear translocation and decreased cancer cell migration. Taken together, we demonstrated that the post-translational modification is required for IKKα nuclear translocation, and the abolishment of the post-translational modification can decrease breast cancer cell migration. This study should provide new insights into the regulation of breast cancer progression and contribute to therapy of breast cancer. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37229 |
全文授權: | 有償授權 |
顯示於系所單位: | 分子醫學研究所 |
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