Role of Daxx in protein folding and tumorigenesis

Daxx 在蛋白质折叠和肿瘤发生中的作用

• 批准号: 10249990
• 负责人: Eric J Brown
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10249990
• 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; Structure; 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

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 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最初由PI鉴定为与死亡受体Fas（CD 95/Apo-1）的细胞内结构域相互作用的衔接蛋白。其他人和我们随后的研究表明DAXX参与了各种细胞凋亡以及无数其他细胞过程。值得注意的是，胰腺神经内分泌肿瘤（PanNET）经常携带DAXX和DAXX相关蛋白ATRX的突变。这些观察结果提出了一个关键问题，即是否存在定义的生物化学活性，该生物化学活性是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）中具有以前未预料到的活性。在这里，我们计划测试的中心假设，DAXX是一种新的催化剂蛋白质折叠（折叠酶），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的蛋白质折叠催化剂活性的分子机制，并阐明其相互作用的合作伙伴和翻译后修饰的调节。其次，肿瘤抑制基因p53在绝大多数肿瘤中失活，在PanNET中很少突变。基于我们的初步数据，我们将测试DAXX是p53的折叠催化剂，促进其稳定性和功能性，以及DAXX的丢失有助于PanNET中这种卓越的肿瘤抑制因子的失活的假设。第三，DAXX和DAXX相互作用蛋白PML都参与端粒（ALT）途径的选择性延长，该途径在包括PanNET在内的各种肿瘤中维持端粒长度。我们以前的研究揭示了PML在错误折叠蛋白的清除中的重要作用。我们将研究DAXX和PML在ALT途径中的合作。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，并为PanNET和其他DAXX相关肿瘤的有效疗法的开发提供有价值的信息。