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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.

摘要