Role of Daxx in protein folding and tumorigenesis

Daxx 在蛋白质折叠和肿瘤发生中的作用

基本信息

批准号：
10495196
负责人：
Xiaolu Yang
金额：
$ 36.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495196
关键词：
ATRX gene Adaptor Signaling Protein Address Animal Model Apoptosis Apoptotic Binding Biochemical Biology CD95 Antigens Cell Culture Techniques Cell Nucleus Cell physiology Cells Complex Coupled Cytosol DAXX gene Data Death Domain Deposition Development Environment Genes Genetic Genetic Transcription Goals Heterochromatin Histones Human Islet Cell Tumor Length Light Link MAPK8 gene Malignant Neoplasms Mammalian Cell Mediating Molecular Molecular Chaperones Molecular Conformation Mutate Mutation Neuroendocrine Cell Nuclear Protein Pathogenesis Pathway interactions Patients Play Post-Translational Protein Processing Protein Conformation Proteins Quality Control Regulation Role Sampling TNFRSF6 gene TP53 gene Telomere Maintenance Telomere Pathway Testing Tumor Suppression Tumor Suppressor Proteins Variant Work base catalyst conformational conversion effective therapy insight misfolded protein nondeletion type alpha-thalassemia/mental retardation syndrome novel prevent protein folding protein misfolding receptor senescence telomere transcription factor PML tumor tumorigenesis

项目摘要

ABSTRACT The overall goal of this application is to elucidate the role of the death domain-associated protein (DAXX) in tumorigenesis. DAXX was initially identified by the PI as an adaptor protein interacting with the intracellular domain of the death receptor Fas (CD95/Apo-1). Subsequent studies by others and us have implicated DAXX in various scenarios of apoptosis, as well as a myriad of other cellular processes. Of note, pancreatic neuroendocrine tumors (PanNETs) frequently harbor mutations in DAXX and the DAXX-associated protein ATRX. These observations raise a critical issue of whether there is a defined biochemical activity that underlies the diverse function of DAXX in general and its tumor suppressive function in PanNETs in particular. Our preliminary data suggests that DAXX possesses a previously unanticipated activity in protein quality control (PQC). Here we plan to test the central hypothesis that DAXX is a novel catalyst for protein folding (foldase) and that the dysregulation of this activity contributes to the pathogenesis of PanNETs. We propose three specific aims. First, we will define the molecular mechanism of the protein folding catalyst activity of DAXX, and elucidate its regulation by interacting partners and post-translational modifications. Second, the tumor suppressor p53, which is inactivated in the vast majority of tumors, is rarely mutated in PanNETs. Based on our preliminary data, we will test the hypothesis that DAXX is a folding catalyst for p53, promoting its stability and functionality, and that the loss of DAXX contributes to the inactivation of this preeminent tumor suppressor in PanNETs. Third, both DAXX and the DAXX-interacting protein PML are involved in the alternative lengthening of telomeres (ALT) pathway, which maintains telomere length in various tumors including PanNETs. Our previous studies reveal an important role of PML in the clearance of misfolded proteins. We will examine the cooperation of DAXX and PML in the ALT pathway. Moreover, we will investigate the role of DAXX in the pathogenesis of PanNETs. Collectively, these aims will address critical issues in DAXX biology and will provide valuable information for the development of effective therapies for PanNETs and other DAXX-associated tumors.

抽象的该应用的总体目标是阐明与死亡结构域相关蛋白（DAXX）在肿瘤发生中的作用。 DAXX最初由PI鉴定为与死亡受体Fas的细胞内结构域相互作用的衔接蛋白（CD95/APO-1）。在各种细胞凋亡以及无数其他细胞过程中，他人和美国的随后研究牵涉到DAXX。值得注意的是，胰腺神经内分泌肿瘤（Pannets）经常在DAXX和与DAXX相关的蛋白ATRX中具有突变。这些观察结果提出了一个关键的问题，即是否存在定义的生化活性，这是DAXX的多样化功能及其在Pannets中的肿瘤抑制功能的基础。我们的初步数据表明，DAXX在蛋白质质量控制（PQC）中具有先前意外的活性。在这里，我们计划测试中心假设，即DAXX是蛋白质折叠（折叠酶）的新型催化剂，并且该活性的失调有助于Pannets的发病机理。我们提出了三个具体目标。首先，我们将定义DAXX蛋白质折叠催化剂活性的分子机制，并通过相互作用的伴侣和翻译后修饰来阐明其调节。其次，在绝大多数肿瘤中灭活的肿瘤抑制p53很少在pannets中突变。基于我们的初步数据，我们将检验以下假设：DAXX是P53的折叠催化剂，促进其稳定性和功能，并且DAXX的丧失有助于使这种巨大的肿瘤抑制器失活。第三，DAXX和DAXX相互作用蛋白PML都参与端粒（ALT）途径的替代延长，该途径在包括Pannets在内的各种肿瘤中保持端粒长度。我们以前的研究揭示了PML在清除错误折叠蛋白质中的重要作用。我们将检查DAXX和PML在ALT途径中的合作。此外，我们将研究DAXX在Pannets发病机理中的作用。总的来说，这些目标将解决DAXX生物学的关键问题，并将为开发Pannets和其他与DAXX相关肿瘤的有效疗法提供有价值的信息。