Regulation of and by the Myc Oncoprotein

Myc 癌蛋白的调节和调节

• 批准号: 7083626
• 负责人: Edward Victor Prochownik
• 金额: $ 28.73万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7083626
• 关键词: biological signal transduction; confocal scanning microscopy; flow cytometry; genetically modified animals; green fluorescent proteins; laboratory mouse; neoplasm /cancer genetics; oncoproteins; oxidative stress; protein protein interaction; protein structure function; protooncogene; redoxin

DESCRIPTION (provided by applicant): The Myc oncoprotein network modulates cell cycle progression, growth, differentiation, apoptosis, and genomic integrity. De-regulation of c-Myc, the prototype member of the family, occurs commonly in many malignancies and is invariably associated with genomic instability and secondary mutations. Understanding the molecular basis for c-Myc's activities will involve characterizing proteins with which it interacts, characterizing the gene products under its control, and determining their roles in mediating c-Myc's multiple phenotypes. Toward the first of these ends, we have recently identified a novel protein, PAG, or peroxiredoxin 1, that interacts with the transcriptional activation domain of c-Myc. PAG inhibits transformation by c-Myc while preserving or even enhancing its other activities. PAG protects cells against oxidative DNA damage and is a tumor suppressor. We have also identified a new transcriptional target for c-Myc, termed MT-MC1, whose over-expression mimics many of the phenotypic properties of c-Myc, including the ability to transform, to alter cellular morphology, to promote apoptosis, to inhibit differentiation, to promote genomic instability, and to regulate some c-Myc target genes. Many of MT-MC1's properties are c-Myc-independent. MT-MC1 thus plays a critical and proximal role in the c-Myc signaling pathway by virtue of its ability to regulate multiple c-Myc functions. Recent evidence also suggests a functional and biochemical connection among c-Myc, PAG, and MT-MC1 with regard to their ability to modulate the response of cells to oxidative stress. Damaged DNA arising from such stress may be a major contributor to tumor generation and/or evolution. In the First Specific Aim of this application, we propose further studies with PAG. These include defining its c-Myc-independent functions, identifying novel proteins with which it interacts, defining the regions necessary for its interaction with c- Myc, and further characterizing a PAG knockout mouse strain. These mice will be used in conjunction with a novel inducible in vivo model of c-Myc-mediated tumorigenesis, regression, and spontaneous recurrence (Tet-Myc mice). In the Second Specific Aim, we propose further studies with MT-MC1. We will examine the effect of MT-MC1 in primary cells, will identify novel MT-MC1-interacting proteins, will further investigate the modular nature of MT-MC1's multiple functions, and will create a conditional MT-MC1 "knockout" mouse strain. Crosses between these animals and either PAG-/- mice or Tet-Myc mice will help to further define in vivo the proposed three-way connection among c-Myc, PAG, and MT-MC1.

描述（由申请人提供）：Myc 癌蛋白网络调节细胞周期进程、生长、分化、细胞凋亡和基因组完整性。 c-Myc（该家族的原型成员）的失调通常发生在许多恶性肿瘤中，并且总是与基因组不稳定和二次突变相关。了解 c-Myc 活性的分子基础将涉及表征与其相互作用的蛋白质、表征其控制下的基因产物以及确定它们在介导 c-Myc 多种表型中的作用。为了实现第一个目标，我们最近发现了一种新蛋白 PAG 或过氧化还原蛋白 1，它与 c-Myc 的转录激活结构域相互作用。 PAG 抑制 c-Myc 的转化，同时保留甚至增强其其他活性。 PAG 可以保护细胞免受 DNA 氧化损伤，并且是一种肿瘤抑制剂。我们还发现了 c-Myc 的一个新转录靶标，称为 MT-MC1，其过表达模仿了 c-Myc 的许多表型特性，包括转化、改变细胞形态、促进细胞凋亡、抑制分化、促进基因组不稳定性以及调节一些 c-Myc 靶基因的能力。 MT-MC1 的许多特性与 c-Myc 无关。因此，MT-MC1 凭借其调节多种 c-Myc 功能的能力，在 c-Myc 信号通路中发挥着至关重要的作用。最近的证据还表明，c-Myc、PAG 和 MT-MC1 之间在调节细胞对氧化应激反应的能力方面存在功能和生化联系。由这种应激引起的受损 DNA 可能是肿瘤产生和/或进化的主要因素。在本申请的第一个具体目标中，我们建议进一步研究 PAG。这些包括定义其不依赖于 c-Myc 的功能、识别与其相互作用的新蛋白质、定义其与 c-Myc 相互作用所需的区域，以及进一步表征 PAG 敲除小鼠品系。这些小鼠将与 c-Myc 介导的肿瘤发生、消退和自发复发的新型诱导体内模型（Tet-Myc 小鼠）结合使用。在第二个具体目标中，我们建议对 MT-MC1 进行进一步研究。我们将检查 MT-MC1 在原代细胞中的作用，将鉴定新的 MT-MC1 相互作用蛋白，将进一步研究 MT-MC1 多种功能的模块化性质，并将创建有条件的 MT-MC1“敲除”小鼠品系。这些动物与 PAG-/- 小鼠或 Tet-Myc 小鼠之间的杂交将有助于在体内进一步确定 c-Myc、PAG 和 MT-MC1 之间所提出的三向连接。