Identification of the protein homeostasis network that controls the quality contr

控制质量控制的蛋白质稳态网络的鉴定

基本信息

  • 批准号:
    8397616
  • 负责人:
  • 金额:
    $ 5.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-01 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Patients afflicted with hereditary von Hippel-Lindau disease develop retinal, cerebellar and spinal cord hemangioblastomas as well as renal carcinomas and tumors of the pancreas and epididymis due to mutations in the gene encoding von Hippel-Lindau tumor suppressor protein (pVHL). pVHL normally functions as an adapter in an E3 ubiquitin ligase complex to regulate the activity of the transcription factor, HIF-1¿. When cellular oxygen levels are reduced, HIF-1¿ is activated and upregulates cellular proliferation factors resulting in cell growth. In the absence of functional pVHL, dysregulation of HIF-1¿ can lead to uncontrolled cell growth regardless of oxygen levels. Studies from the Frydman laboratory have demonstrated that proper folding and functionality of pVHL requires an interaction between pVHL and the chaperone Hsp70 and the large cytosolic heterooligomeric chaperonin TriC. Folded pVHL is then competent to form a complex with elongins B and C (herein elongin BC), a step that is required for pVHL stability. The pVHL-elongin BC complex (VBC), when incorporated into the SCF E3 ubiquitin ligase complex, directs the proteolytic degradation of HIF-1¿ in the presence of oxygen. Thus, proper folding and functionality of pVHL involves several protein quality control "checkpoints" mediated by chaperone and proteasomal machinery. Importantly, some of the mutants leading to VHL disease have the potential to achieve folding, but fail to do so through the action of these quality control checkpoints that result in their degradation. The mechanism of proteolytic degradation of pVHL mutants is unclear. The long-term goal of this research is to determine how cellular protein folding and degradation machinery cooperate to maintain quality control of the tumor suppressor protein pVHL. Here we propose to determine the chaperone and proteolytic degradation quality control requirements of tumor-causing mutations in the easily manipulated yeast system and then determine if these mechanisms are conserved in mammalian cells. This understanding may lead to therapeutic strategies to restore the function of these mutant proteins in affected patients. Since other pathological processes, including other cancers, are caused by mutations that affect the folding or stability of key regulatory proteins, the results obtained for VHL may provide a paradigm with broad conceptual and therapeutic implications. PUBLIC HEALTH RELEVANCE: Patients with hereditary von Hippel-Lindau disease have the potential to develop a variety of tumors including hemangioblastomas in retinal, cerebellar and spinal cord tissue as well as renal carcinomas and tumors of the pancreas and epididymis. The basis of tumor formation in these patients is due to mutations in the von Hippel- Lindau tumor suppressor protein (pVHL), a protein that normally functions to keep cell division in check. In this proposal, we will determine the mechanism by which the cell recognizes and processes mutant pVHL protein in an effort to identify therapies by which normal pVHL function can be restored in human cells.
描述(由申请人提供):由于编码von Hippel-Lindau肿瘤抑制蛋白(pVHL)的基因突变,患有遗传性von Hippel-Lindau病的患者发生视网膜、小脑和脊髓血管母细胞瘤以及肾癌和胰腺及附睾肿瘤。pVHL通常作为E3泛素连接酶复合物中的接头发挥作用,以调节转录因子HIF-1?的活性。当细胞氧水平降低时,HIF-1?被激活并上调细胞增殖因子,导致细胞生长。在没有功能性pVHL的情况下,HIF-1的失调可以导致不受控制的细胞生长,而不管氧水平如何。来自Frydman实验室的研究已经证明,pVHL的正确折叠和功能需要pVHL与分子伴侣Hsp 70和大的胞质异源寡聚分子伴侣TriC之间的相互作用。然后折叠的pVHL能够与延伸蛋白B和C(本文中为延伸蛋白BC)形成复合物,这是pVHL稳定性所需的步骤。pVHL-延伸蛋白BC复合物(VBC),当掺入SCF E3泛素连接酶复合物中时,在氧存在下指导HIF-1?的蛋白水解降解。因此,pVHL的正确折叠和功能性涉及几个由伴侣蛋白和蛋白酶体机制介导的蛋白质质量控制“检查点”。重要的是,导致VHL疾病的一些突变体具有实现折叠的潜力,但通过这些质量控制检查点的作用而未能实现折叠,从而导致其降解。pVHL突变体的蛋白水解降解机制尚不清楚。这项研究的长期目标是确定细胞蛋白质折叠和降解机制如何合作,以保持肿瘤抑制蛋白pVHL的质量控制。在这里,我们建议确定的伴侣蛋白和蛋白水解降解质量控制要求的肿瘤引起的突变,在容易操作的酵母系统,然后确定这些机制是否在哺乳动物细胞中是保守的。这种理解可能会导致治疗策略,以恢复这些突变蛋白在受影响的患者的功能。由于其他病理过程,包括其他癌症,是由影响关键调控蛋白的折叠或稳定性的突变引起的,因此VHL获得的结果可能提供具有广泛概念和治疗意义的范例。 公共卫生相关性:患有遗传性von Hippel-Lindau病的患者有可能发展成各种肿瘤,包括视网膜、小脑和脊髓组织中的血管母细胞瘤以及肾癌和胰腺和附睾肿瘤。这些患者中肿瘤形成的基础是由于von Hippel-Lindau肿瘤抑制蛋白(pVHL)的突变,pVHL是一种正常功能是保持细胞分裂的蛋白质。在这个提议中,我们将确定细胞识别和处理突变pVHL蛋白的机制,以确定可以在人类细胞中恢复正常pVHL功能的疗法。

项目成果

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Christine Marie Livingston其他文献

Christine Marie Livingston的其他文献

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{{ truncateString('Christine Marie Livingston', 18)}}的其他基金

Identification of the protein homeostasis network that controls the quality contr
控制质量控制的蛋白质稳态网络的鉴定
  • 批准号:
    8540099
  • 财政年份:
    2012
  • 资助金额:
    $ 5.22万
  • 项目类别:

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