本文選題：Parkin + 乳腺癌��； 參考：《南開大學》2010年博士論文

【摘要】：Parkin基因(也被稱為PARK2)位于6號染色體的25.2-27區(qū)的脆性位點區(qū)域,是一個編碼泛素連接酶的基因,能夠促進蛋白底物的泛素化,使之通過蛋白酶體進行降解。多年的研究證明Parkin基因的突變是導(dǎo)致帕金森癥發(fā)生的主要原因之一。Parkin在多種腫瘤中的表達顯著降低或者不表達,并且有報道表明Parkin表達的降低主要是由于它的啟動子的異常甲基化所引起的。這些實驗結(jié)果表明Parkin可能是一個潛在的腫瘤抑制因子。看來,Parkin在帕金森癥以及癌癥發(fā)生過程中都起重要作用,其分子機制有待進一步研究。 最近的報道表明,Parkin是一個微管結(jié)合蛋白,并且Parkin與微管的結(jié)合不受Parkin泛素連接酶活性喪失的點突變的影響。微管與Parkin的這種共定位關(guān)系有可能使Parkin錨定于細胞質(zhì)中從而調(diào)節(jié)Parkin的泛素連接酶活性�？紤]到微管在細胞內(nèi)的多種重要作用以及微管作為腫瘤化療靶點的研究,我們推斷Parkin與微管的結(jié)合可能具有重要的生理意義,有可能會影響紫杉醇等以微管為靶點的抗腫瘤藥物的敏感性。在我們的研究中發(fā)現(xiàn)Parkin能夠結(jié)合在微管的外部,增強了微管與紫杉醇之間的結(jié)合,從而增強了由紫杉醇所誘導(dǎo)的微管的組裝以及微管的穩(wěn)定性。進一步研究的實驗結(jié)果表明Parkin能夠增加由紫杉醇所誘導(dǎo)的細胞多核化以及細胞凋亡,使得乳腺癌細胞對紫杉醇更加敏感。更為重要的是,在臨床上采用紫杉醇聯(lián)合用藥化療的病人組織樣本中,Parkin的表達與腫瘤患者的病理反應(yīng)成正相關(guān)。并且在原代培養(yǎng)的乳腺癌細胞中,Parkin的表達水平與紫杉醇的敏感性也是正相關(guān)的。這些研究表明Parkin可以促進乳腺癌對紫杉醇藥物的敏感性,因此Parkin的表達水平可以做為一個診斷的標志,幫助預(yù)測乳腺癌患者是否適合含有紫杉醇的方案進行化療。除此之外,我們的研究還表明,Parkin可以作為化療藥物開發(fā)的靶點,用以提高紫杉醇的敏感性。 Parkin基因的突變是導(dǎo)致帕金森癥發(fā)生的主要原因之一,50%以上的早發(fā)性青少年帕金森癥中都檢測到了Parkin的突變。Parkin的突變導(dǎo)致帕金森癥的原因可能是由于Parkin的突變致使泛素連接酶活性喪失,使得底物蛋白不能夠被泛素化通過蛋白酶體進行降解,從而在細胞內(nèi)過度累積,對細胞產(chǎn)生了極大的毒性。近年來的研究證明帕金森癥患者中線粒體的形態(tài),動態(tài)性以及功能都會發(fā)生異常。線粒體是一個高度動態(tài)性的器官,處于不斷的斷裂與融合的過程中,提供生物體所需要的大部分能量。線粒體動態(tài)性的失調(diào)與神經(jīng)元細胞的存活以及多種神經(jīng)性疾病的發(fā)生相關(guān)。大量的實驗證明Parkin在調(diào)節(jié)線粒體動態(tài)性上起到了重要的作用,它能夠與線粒體動態(tài)性相關(guān)蛋白相互作用來調(diào)節(jié)線粒體的斷裂或者融合,然而調(diào)節(jié)的具體機制尚未明確,并且也還沒有發(fā)現(xiàn)有一個線粒體相關(guān)的蛋白會在帕金森癥患者的腦部發(fā)生累積。 在我們的研究中,發(fā)現(xiàn)Parkin能夠與線粒體斷裂相關(guān)蛋白Drp1相互作用,通過泛素48位賴氨酸形成的多聚泛素化鏈介導(dǎo)Drp1的泛素化,使其通過蛋白酶體進行降解。沉默細胞內(nèi)的Parkin能夠使Drp1的表達水平明顯的升高,從而導(dǎo)致線粒體的片斷化。除此之外,用可以誘導(dǎo)帕金森癥模型的神經(jīng)毒素處理細胞時,能夠使Parkin的表達水平明顯的降低,而Drp1的表達水平顯著增高。當沉默細胞內(nèi)Drp1的表達水平時,能夠抑制由神經(jīng)毒素所誘導(dǎo)的線粒體的片斷化以及細胞凋亡,并且能夠有效的抑制帕金森癥小鼠腦部黑質(zhì)密質(zhì)層部位多巴胺神經(jīng)元的丟失。更為重要的是,通過免疫組化和生化分析帕金森癥病人的臨床組織樣本,我們發(fā)現(xiàn)Parkin與Drp1的表達水平是負相關(guān)的,Drp1的表達水平明顯的增加,而Parkin的表達水平顯著降低。這些證據(jù)表明Drp1是一個典型的Parkin的底物,Parkin表達水平的降低以及突變能夠?qū)е翫rp1蛋白的累積,從而使線粒體發(fā)生片斷化,功能異常。我們的研究揭示了帕金森癥中Parkin基因的突變導(dǎo)致線粒體形態(tài)功能異常的重要機制。
[Abstract]:The Parkin gene (also known as PARK2), a fragile site in the 25.2-27 region of chromosome 6, is a gene encoding a ubiquitin ligase that promotes ubiquitination of protein substrates and degradate them through proteasomes. Years of studies have shown that the mutation of the Parkin gene is one of the main causes of the occurrence of Parkinson's disease,.Parkin The expression of a variety of tumors is significantly reduced or unexpressed, and there have been reports that the decrease in Parkin expression is mainly due to the abnormal methylation of its promoter. These results suggest that Parkin may be a potential tumor suppressor. It appears that Parkin plays an important role in the process of Parkinson's and cancer. Its molecular mechanism remains to be further studied.
Recent reports suggest that Parkin is a microtubule binding protein, and the combination of Parkin with microtubules is not affected by the point mutation of the loss of Parkin ubiquitin ligase activity. This colocalization relationship between microtubules and Parkin may cause Parkin to be anchored in the cytoplasm to regulate the ubiquitin ligase activity of Parkin. A variety of important roles and microtubules as a target for cancer chemotherapy, we infer that the combination of Parkin and microtubules may have important physiological significance and may affect the sensitivity of paclitaxel and other antitumor drugs targeting microtubules. In our study, we found that Parkin can be combined with the external microtubules to enhance microtubules and purple. The combination of taxol enhanced the assembly of microtubules and the stability of microtubules induced by taxol. Further studies showed that Parkin could increase cell nucleation and cell apoptosis induced by taxol, making breast cancer cells more sensitive to taxol. The expression of Parkin was positively related to the pathological response of the tumor patients in the tissue samples of the patients treated with taxol, and the expression level of Parkin was also positively related to the sensitivity of taxol in the primary cultured breast cancer cells. These studies suggest that Parkin can promote the sensitivity of breast cancer to paclitaxel drugs, so Par The expression level of kin can be used as a diagnostic marker to help predict whether patients with breast cancer are suitable for chemotherapy with paclitaxel. Our study also suggests that Parkin can be used as a target for the development of chemotherapeutic drugs to improve the sensitivity of taxol.
Mutation of the Parkin gene is one of the main causes of the occurrence of Parkinson's disease. More than 50% of early adolescent Parkinson's disease has detected a mutation of the Parkin mutation.Parkin, which may cause the loss of the ubiquitin ligase activity due to the mutation of the Parkin, so that the substrate protein can not be generalized by ubiquitination. The proteasome is degraded and overaccumulated in the cell, producing great toxicity to the cells. In recent years, studies have shown that the morphology, dynamics and function of mitochondria in the patients with Parkinson's disease are abnormal. Mitochondria are a highly dynamic organ that provides organisms in the process of breaking and fusion. Most of the energy needed. The imbalance of mitochondrial dynamics is associated with the survival of neurons and the occurrence of a variety of neuropathic diseases. A large number of experiments have shown that Parkin plays an important role in regulating mitochondrial dynamics, and it can interact with mitochondrial dynamic related proteins to regulate mitochondrial disruption or fusion. However, the specific mechanism of regulation is not yet clear, and no mitochondrial associated protein has been found to accumulate in the brain of patients with Parkinson's disease.
In our study, we found that Parkin can interact with mitochondrial fracture related protein Drp1 and mediate the ubiquitination of Drp1 through a polyubiquitin 48 - bit lysine - based polyubiquitin chain that degradates it through proteasome. The silence of Parkin in cells can cause a flat rise in the expression of Drp1, leading to the fragmentation of the mitochondria. In addition, when the neurotoxin, which can induce Parkinson's disease model, can reduce the expression level of Parkin obviously, and the expression level of Drp1 is significantly higher. When the expression level of Drp1 in the silent cell, it can inhibit the fragmentation of the mitochondria and apoptosis induced by the neurotoxin, and can be used. The loss of dopamine neurons in the substantia nigra of the brain of Parkinson's mice was inhibited. More importantly, we found that the expression level of Parkin was negatively correlated with the expression level of Drp1 by immunohistochemical and biochemical analysis of the clinical tissue samples of the patients with Parkinson's disease. The expression level of Drp1 was significantly increased, while the expression level of Parkin was significant. These evidences suggest that Drp1 is a typical substrate for Parkin, the decrease of Parkin expression level and the mutation can lead to the accumulation of Drp1 protein, resulting in the fragmentation and dysfunction of mitochondria. Our study revealed the important mechanism of the abnormal mitochondrial morphologic function in Parkinson's disease.
【學位授予單位】：南開大學
【學位級別】：博士
【學位授予年份】：2010
【分類號】：R329;Q51

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