Regulation of and by the Myc Oncoprotein

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、凋亡和基因组完整性。c-Myc是家族的原型成员，其去调控在许多恶性肿瘤中普遍发生，并且总是与基因组不稳定和继发性突变相关。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，并确定它们在介导c-Myc的多种表型中的作用。在第一个方面，我们最近发现了一种新的蛋白，PAG或过氧化物还氧蛋白1，它与c-Myc的转录激活域相互作用。PAG抑制c-Myc的转化，同时保持甚至增强其其他活性。PAG保护细胞免受DNA氧化损伤，是一种肿瘤抑制因子。我们还确定了c-Myc的一个新的转录靶点，称为MT-MC1，其过度表达模仿了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和调节一些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信号通路中起着关键和近端作用。最近的证据还表明，c-Myc、PAG和MT-MC1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。这种压力引起的DNA损伤可能是肿瘤产生和/或进化的主要原因。在本应用的第一个具体目标中，我们提出了进一步研究PAG的建议。这些包括确定其与c-Myc无关的功能，鉴定与其相互作用的新蛋白质，确定其与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。这些小鼠将与一种新的c- myc介导的肿瘤发生、消退和自发复发的体内诱导模型（Tet-Myc小鼠）结合使用。在第二个具体目标中，我们提出了对MT-MC1的进一步研究。我们将研究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，并将创建一个条件MT-MC1“敲除”小鼠品系。这些动物与PAG-/-小鼠或Tet-Myc小鼠的杂交将有助于进一步在体内确定c-Myc、PAG和MT-MC1之间的三向连接。

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.