Parkin与细胞结构相关蛋白相互作用：分子机制与功能
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摘要
Parkin基因(也被称为PARK2)位于6号染色体的25.2-27区的脆性位点区域,是一个编码泛素连接酶的基因,能够促进蛋白底物的泛素化,使之通过蛋白酶体进行降解。多年的研究证明Parkin基因的突变是导致帕金森症发生的主要原因之一。Parkin在多种肿瘤中的表达显著降低或者不表达,并且有报道表明Parkin表达的降低主要是由于它的启动子的异常甲基化所引起的。这些实验结果表明Parkin可能是一个潜在的肿瘤抑制因子。看来,Parkin在帕金森症以及癌症发生过程中都起重要作用,其分子机制有待进一步研究。
最近的报道表明,Parkin是一个微管结合蛋白,并且Parkin与微管的结合不受Parkin泛素连接酶活性丧失的点突变的影响。微管与Parkin的这种共定位关系有可能使Parkin锚定于细胞质中从而调节Parkin的泛素连接酶活性。考虑到微管在细胞内的多种重要作用以及微管作为肿瘤化疗靶点的研究,我们推断Parkin与微管的结合可能具有重要的生理意义,有可能会影响紫杉醇等以微管为靶点的抗肿瘤药物的敏感性。在我们的研究中发现Parkin能够结合在微管的外部,增强了微管与紫杉醇之间的结合,从而增强了由紫杉醇所诱导的微管的组装以及微管的稳定性。进一步研究的实验结果表明Parkin能够增加由紫杉醇所诱导的细胞多核化以及细胞凋亡,使得乳腺癌细胞对紫杉醇更加敏感。更为重要的是,在临床上采用紫杉醇联合用药化疗的病人组织样本中,Parkin的表达与肿瘤患者的病理反应成正相关。并且在原代培养的乳腺癌细胞中,Parkin的表达水平与紫杉醇的敏感性也是正相关的。这些研究表明Parkin可以促进乳腺癌对紫杉醇药物的敏感性,因此Parkin的表达水平可以做为一个诊断的标志,帮助预测乳腺癌患者是否适合含有紫杉醇的方案进行化疗。除此之外,我们的研究还表明,Parkin可以作为化疗药物开发的靶点,用以提高紫杉醇的敏感性。
Parkin基因的突变是导致帕金森症发生的主要原因之一,50%以上的早发性青少年帕金森症中都检测到了Parkin的突变。Parkin的突变导致帕金森症的原因可能是由于Parkin的突变致使泛素连接酶活性丧失,使得底物蛋白不能够被泛素化通过蛋白酶体进行降解,从而在细胞内过度累积,对细胞产生了极大的毒性。近年来的研究证明帕金森症患者中线粒体的形态,动态性以及功能都会发生异常。线粒体是一个高度动态性的器官,处于不断的断裂与融合的过程中,提供生物体所需要的大部分能量。线粒体动态性的失调与神经元细胞的存活以及多种神经性疾病的发生相关。大量的实验证明Parkin在调节线粒体动态性上起到了重要的作用,它能够与线粒体动态性相关蛋白相互作用来调节线粒体的断裂或者融合,然而调节的具体机制尚未明确,并且也还没有发现有一个线粒体相关的蛋白会在帕金森症患者的脑部发生累积。
在我们的研究中,发现Parkin能够与线粒体断裂相关蛋白Drp1相互作用,通过泛素48位赖氨酸形成的多聚泛素化链介导Drp1的泛素化,使其通过蛋白酶体进行降解。沉默细胞内的Parkin能够使Drp1的表达水平明显的升高,从而导致线粒体的片断化。除此之外,用可以诱导帕金森症模型的神经毒素处理细胞时,能够使Parkin的表达水平明显的降低,而Drp1的表达水平显著增高。当沉默细胞内Drp1的表达水平时,能够抑制由神经毒素所诱导的线粒体的片断化以及细胞凋亡,并且能够有效的抑制帕金森症小鼠脑部黑质密质层部位多巴胺神经元的丢失。更为重要的是,通过免疫组化和生化分析帕金森症病人的临床组织样本,我们发现Parkin与Drp1的表达水平是负相关的,Drp1的表达水平明显的增加,而Parkin的表达水平显著降低。这些证据表明Drp1是一个典型的Parkin的底物,Parkin表达水平的降低以及突变能够导致Drp1蛋白的累积,从而使线粒体发生片断化,功能异常。我们的研究揭示了帕金森症中Parkin基因的突变导致线粒体形态功能异常的重要机制。
Parkin is an E3 ubiquitin ligase encoded by the Parkin gene (also called PARK2, located at 6q25.2-q27) and is involved in the pathogenesis of both Parkinson's disease and the development of cancer. Reduced expression and inactivation of Parkin are frequently observed in human cancers. It is reported that Parkin expression can be epigenetically regulated; its expression can be reduced due to abnormal DNA methylation. These studies suggest that Parkin may play a role in tumour suppression. Although the precise mechanisms of how Parkin is involved in the development of Parkinson's disease and cancer remain elusive, alterations in its ubiquitin ligase activity are evident in a significant proportion of these patients.
In addition to its function as an ubiquitin ligase, Parkin has recently been identified as a molecule capable of interacting with microtubules. However, the biological implication of the Parkin-microtubule axis has been poorly explored. In this study, we report for the first time that Parkin modulates sensitivity of the chemotherapeutic agent paclitaxel in breast cancer, via a microtubule-dependent mechanism. Our data reveal that Parkin binds to the outer surface of microtubules and increases paclitaxel-microtubule interaction, resulting in enhanced paclitaxel-induced microtubule assembly and stabilization. Our data further show that Parkin promotes the activity of paclitaxel to trigger multinucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Moreover, Parkin expression correlates with the pathological response of tumours to preoperative paclitaxel-containing chemotherapy. In addition, expression of Parkin also correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells. Our results identify Parkin as a novel mediator of paclitaxel sensitivity in breast cancer. In addition, our study suggests that patients harbouring tumours with high Parkin level would be more likely to benefit from paclitaxel-containing regimens.
Parkin gene mutations have been implicated in autosomal-recessive early-onset parkinsonism and lead to specific degeneration of dopaminergic neurons in midbrain. A putative mechanism by which mutations of Parkin cause PD would be abnormal accumulation of its substrates due to altered E3 ligase activity for ubiquitin-proteasome dependent protein turnover. Over the past few decades, accumulating evidence has suggested that mitochondrial dysfunction and the resulting oxidative damage which occur prior to the neuronal loss are associated with PD. Mitochondria undergo frequent fission, fusion, and redistribution throughout the cytoplasm in response to the energy needs. Strong evidence has showed that Parkin plays a critical role in regulating mitochondrial fission and fusion and mitochondrial quality control. However, the precise mechanism of how parkin regulates mitochondrial dynamics remains a subject of debate, and so far, no substrate responsible for altered mitochondrial dynamics and functions was found to be accumulated due to the mutation of Parkin.
In our study, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), a key molecule responsible for mitochondrial fission, for promoting its proteasome-dependent degradation. Knockdown of Parkin expression significantly increases the level of Drpl leading to mitochondrial fragmentation. In addition, neurotoxins known to induce PD reduce the level of Parkin and remarkably enhance the expression of Dip1 whereas knockdown of Drpl inhibits neurotoxin-induced cell death. Interestingly, inhibition of Drpl activity prevents MPP+-induced mitochondrial fragmentation and neuronal loss in cell and animal PD model systems. Immunohistochemical and biochemical analyses of PD patient brain samples further confirm the inverse correlation between Parkin and Drp1. These results identify Drp1 as a novel substrate of Parkin and uncover a novel mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of PD.
最近的报道表明,Parkin是一个微管结合蛋白,并且Parkin与微管的结合不受Parkin泛素连接酶活性丧失的点突变的影响。微管与Parkin的这种共定位关系有可能使Parkin锚定于细胞质中从而调节Parkin的泛素连接酶活性。考虑到微管在细胞内的多种重要作用以及微管作为肿瘤化疗靶点的研究,我们推断Parkin与微管的结合可能具有重要的生理意义,有可能会影响紫杉醇等以微管为靶点的抗肿瘤药物的敏感性。在我们的研究中发现Parkin能够结合在微管的外部,增强了微管与紫杉醇之间的结合,从而增强了由紫杉醇所诱导的微管的组装以及微管的稳定性。进一步研究的实验结果表明Parkin能够增加由紫杉醇所诱导的细胞多核化以及细胞凋亡,使得乳腺癌细胞对紫杉醇更加敏感。更为重要的是,在临床上采用紫杉醇联合用药化疗的病人组织样本中,Parkin的表达与肿瘤患者的病理反应成正相关。并且在原代培养的乳腺癌细胞中,Parkin的表达水平与紫杉醇的敏感性也是正相关的。这些研究表明Parkin可以促进乳腺癌对紫杉醇药物的敏感性,因此Parkin的表达水平可以做为一个诊断的标志,帮助预测乳腺癌患者是否适合含有紫杉醇的方案进行化疗。除此之外,我们的研究还表明,Parkin可以作为化疗药物开发的靶点,用以提高紫杉醇的敏感性。
Parkin基因的突变是导致帕金森症发生的主要原因之一,50%以上的早发性青少年帕金森症中都检测到了Parkin的突变。Parkin的突变导致帕金森症的原因可能是由于Parkin的突变致使泛素连接酶活性丧失,使得底物蛋白不能够被泛素化通过蛋白酶体进行降解,从而在细胞内过度累积,对细胞产生了极大的毒性。近年来的研究证明帕金森症患者中线粒体的形态,动态性以及功能都会发生异常。线粒体是一个高度动态性的器官,处于不断的断裂与融合的过程中,提供生物体所需要的大部分能量。线粒体动态性的失调与神经元细胞的存活以及多种神经性疾病的发生相关。大量的实验证明Parkin在调节线粒体动态性上起到了重要的作用,它能够与线粒体动态性相关蛋白相互作用来调节线粒体的断裂或者融合,然而调节的具体机制尚未明确,并且也还没有发现有一个线粒体相关的蛋白会在帕金森症患者的脑部发生累积。
在我们的研究中,发现Parkin能够与线粒体断裂相关蛋白Drp1相互作用,通过泛素48位赖氨酸形成的多聚泛素化链介导Drp1的泛素化,使其通过蛋白酶体进行降解。沉默细胞内的Parkin能够使Drp1的表达水平明显的升高,从而导致线粒体的片断化。除此之外,用可以诱导帕金森症模型的神经毒素处理细胞时,能够使Parkin的表达水平明显的降低,而Drp1的表达水平显著增高。当沉默细胞内Drp1的表达水平时,能够抑制由神经毒素所诱导的线粒体的片断化以及细胞凋亡,并且能够有效的抑制帕金森症小鼠脑部黑质密质层部位多巴胺神经元的丢失。更为重要的是,通过免疫组化和生化分析帕金森症病人的临床组织样本,我们发现Parkin与Drp1的表达水平是负相关的,Drp1的表达水平明显的增加,而Parkin的表达水平显著降低。这些证据表明Drp1是一个典型的Parkin的底物,Parkin表达水平的降低以及突变能够导致Drp1蛋白的累积,从而使线粒体发生片断化,功能异常。我们的研究揭示了帕金森症中Parkin基因的突变导致线粒体形态功能异常的重要机制。
Parkin is an E3 ubiquitin ligase encoded by the Parkin gene (also called PARK2, located at 6q25.2-q27) and is involved in the pathogenesis of both Parkinson's disease and the development of cancer. Reduced expression and inactivation of Parkin are frequently observed in human cancers. It is reported that Parkin expression can be epigenetically regulated; its expression can be reduced due to abnormal DNA methylation. These studies suggest that Parkin may play a role in tumour suppression. Although the precise mechanisms of how Parkin is involved in the development of Parkinson's disease and cancer remain elusive, alterations in its ubiquitin ligase activity are evident in a significant proportion of these patients.
In addition to its function as an ubiquitin ligase, Parkin has recently been identified as a molecule capable of interacting with microtubules. However, the biological implication of the Parkin-microtubule axis has been poorly explored. In this study, we report for the first time that Parkin modulates sensitivity of the chemotherapeutic agent paclitaxel in breast cancer, via a microtubule-dependent mechanism. Our data reveal that Parkin binds to the outer surface of microtubules and increases paclitaxel-microtubule interaction, resulting in enhanced paclitaxel-induced microtubule assembly and stabilization. Our data further show that Parkin promotes the activity of paclitaxel to trigger multinucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Moreover, Parkin expression correlates with the pathological response of tumours to preoperative paclitaxel-containing chemotherapy. In addition, expression of Parkin also correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells. Our results identify Parkin as a novel mediator of paclitaxel sensitivity in breast cancer. In addition, our study suggests that patients harbouring tumours with high Parkin level would be more likely to benefit from paclitaxel-containing regimens.
Parkin gene mutations have been implicated in autosomal-recessive early-onset parkinsonism and lead to specific degeneration of dopaminergic neurons in midbrain. A putative mechanism by which mutations of Parkin cause PD would be abnormal accumulation of its substrates due to altered E3 ligase activity for ubiquitin-proteasome dependent protein turnover. Over the past few decades, accumulating evidence has suggested that mitochondrial dysfunction and the resulting oxidative damage which occur prior to the neuronal loss are associated with PD. Mitochondria undergo frequent fission, fusion, and redistribution throughout the cytoplasm in response to the energy needs. Strong evidence has showed that Parkin plays a critical role in regulating mitochondrial fission and fusion and mitochondrial quality control. However, the precise mechanism of how parkin regulates mitochondrial dynamics remains a subject of debate, and so far, no substrate responsible for altered mitochondrial dynamics and functions was found to be accumulated due to the mutation of Parkin.
In our study, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), a key molecule responsible for mitochondrial fission, for promoting its proteasome-dependent degradation. Knockdown of Parkin expression significantly increases the level of Drpl leading to mitochondrial fragmentation. In addition, neurotoxins known to induce PD reduce the level of Parkin and remarkably enhance the expression of Dip1 whereas knockdown of Drpl inhibits neurotoxin-induced cell death. Interestingly, inhibition of Drpl activity prevents MPP+-induced mitochondrial fragmentation and neuronal loss in cell and animal PD model systems. Immunohistochemical and biochemical analyses of PD patient brain samples further confirm the inverse correlation between Parkin and Drp1. These results identify Drp1 as a novel substrate of Parkin and uncover a novel mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of PD.
引文
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