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是该家族的原型成员，它的缺失在许多恶性肿瘤中普遍存在，并且总是与基因组的不稳定和继发性突变有关。了解c-Myc活性的分子基础将包括鉴定与其相互作用的蛋白质，鉴定其控制下的基因产物，并确定它们在调节c-Myc多种表型中的作用。对于第一个末端，我们最近发现了一种新的蛋白质，PAG，或过氧化还蛋白1，它与c-Myc的转录激活结构域相互作用。PAG在抑制c-Myc转化的同时，保留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。我们还发现了c-Myc的一个新的转录靶点，称为MT-MC1，它的过度表达模仿了c-Myc的许多表型特征，包括转化、改变细胞形态、促进凋亡、抑制分化、促进基因组不稳定性以及调节一些c-Myc靶基因。MT-MC1的许多S性质是c-Myc无关的。因此，MT-MC1通过调节多种c-Myc功能，在c-Myc信号通路中起着关键的和最近的作用。最近的证据也表明，c-Myc、PAG和MT-MC1之间的功能和生化联系与它们调节细胞对氧化应激的反应的能力有关。这种应激引起的DNA损伤可能是肿瘤发生和/或演变的主要因素。在本申请的第一个具体目标中，我们建议对PAG进行进一步的研究。这些包括定义其c-Myc非依赖的功能，识别与其相互作用的新蛋白，定义其与c-Myc相互作用所需的区域，以及进一步鉴定PAG基因敲除小鼠品系。这些小鼠将与一种新的可诱导的c-Myc介导的肿瘤发生、退化和自发复发的体内模型(Tet-Myc小鼠)一起使用。在第二个具体目标中，我们建议对MT-MC1进行进一步的研究。我们将检测MT-MC1在原代细胞中的作用，将鉴定与MT-MC1相互作用的新蛋白，将进一步研究MT-MC1‘S多功能的模块化性质，并将创造一个条件MT-MC1“基因敲除”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定义所提出的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.