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：
10689110
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/10689110
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 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 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.

抽象的本申请的总体目标是阐明死亡结构域相关蛋白（DAXX）在肿瘤发生中的作用。 DAXX 最初被 PI 鉴定为与死亡受体 Fas (CD95/Apo-1) 胞内结构域相互作用的衔接蛋白。我们和其他人的后续研究表明 DAXX 与细胞凋亡的各种情况以及无数其他细胞过程有关。值得注意的是，胰腺神经内分泌肿瘤 (PanNET) 经常含有 DAXX 和 DAXX 相关蛋白 ATRX 突变。这些观察结果提出了一个关键问题：是否存在明确的生化活性，该活性是 DAXX 的多种功能的基础，特别是其在 PanNET 中的肿瘤抑制功能。我们的初步数据表明 DAXX 在蛋白质质量控制 (PQC) 方面具有先前未预料到的活性。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，并且这种活性的失调有助于 PanNET 的发病机制。我们提出三个具体目标。首先，我们将定义DAXX蛋白质折叠催化活性的分子机制，并阐明其通过相互作用伙伴和翻译后修饰的调节。其次，肿瘤抑制因子 p53 在绝大多数肿瘤中失活，但在 PanNET 中很少发生突变。根据我们的初步数据，我们将检验以下假设：DAXX 是 p53 的折叠催化剂，可促进其稳定性和功能，并且 DAXX 的缺失会导致 PanNET 中这种卓越的肿瘤抑制因子失活。第三，DAXX和DAXX相互作用蛋白PML都参与端粒选择性延长（ALT）途径，该途径维持包括PanNET在内的各种肿瘤中的端粒长度。我们之前的研究揭示了 PML 在清除错误折叠蛋白中的重要作用。我们将考察 DAXX 和 PML 在 ALT 通路上的合作。此外，我们将研究 DAXX 在 PanNET 发病机制中的作用。总的来说，这些目标将解决 DAXX 生物学中的关键问题，并将为开发 PanNET 和其他 DAXX 相关肿瘤的有效疗法提供有价值的信息。