Nrdp1 Protein Degradation Pathway in Mammary Tumor Progression

ErbB生长因子家族成员的异常过表达和伴随激活 因子受体酪氨酸激酶在促进多种生物的生长和发展中起关键作用 实体肿瘤类型。拟议研究的长期目标是了解 调节ErbB诱导的肿瘤进展的新的蛋白质降解途径。一个中环 该途径的组成部分是一种名为Nrdpl的环指E3泛素连接酶，它介导 ErbB受体的泛素化，从而促进其向降解细胞的运输 车厢。指导这些研究的假设是Nrdp1蛋白降解途径 通过调节受体水平调节ErbB介导的细胞生长信号 退化。当前资助期的两个首要目标是了解 调节Nrdp1活性的分子机制，并了解 ErbB受体诱导的Nrdp1通路诱导乳腺肿瘤的生长和发展。这些 这些目标将有三个具体目标。1)Nrdp1的稳定性和活性的调节 将使用生化方法检测生长因子、信号通路和脱泛素酶。 和分子生物学方法。参与该途径的蛋白质之间的相互作用将 也要接受检查。2)Nrdp1途径组分的过度表达或缺失对细胞的影响 将检测培养的小鼠和人乳腺肿瘤细胞系的生长特性 使用检测增殖、存活、运动和侵袭的方法。3)Nrdpl对 ErbB诱导的乳腺肿瘤在转基因小鼠模型中的生长将被确定。 这些研究将评估野生型Nrdpl在小鼠乳腺中的过度表达 能抑制ErbB诱导的乳腺肿瘤的潜伏期、生长和转移，以及是否 显性负性Nrdp1基因的过表达可诱导乳腺肿瘤的形成或增强 ErbB诱导的肿瘤的潜伏期或生长。这些研究的结果可能牵涉到Nrdpl 途径作为肿瘤细胞生长和进展的抑制者，进而表明恢复或 增强肿瘤的通路功能可以提供治疗上的好处。

The aberrant overexpression and concomitant activation of members of the ErbB family of growth factor receptor tyrosine kinases plays key roles in promoting the growth and progression of a variety of solid tumor types. The long-term objective of the proposed studies is to understand the role of a novel protein degradation pathway in regulating ErbB-induced tumor progression. A central component of the pathway is a RING finger E3 ubiquitin ligase called Nrdpl that mediates the ubiquitination of ErbB receptors, thereby promoting their trafficking to degradative cellular compartments. The hypothesis guiding these studies is that the Nrdpl protein degradation pathway regulates ErbB-mediated cellular growth signaling by governing receptor levels through degradation. The two overarching goals for the current funding period are to understand the molecular mechanisms by which Nrdpl activity is regulated, and to understand the contribution of the Nrdpl pathway to ErbB receptor-induced mammary tumor growth and progression. These goals will be addressed with three specific aims. 1) The regulation of Nrdpl stability and activity by growth factors, signaling kinases and deubiquitinating enzymes will be examined using biochemical and molecular biological methods. The interactions among proteins involved in the pathway will also be examined. 2) The impact of the overexpression or loss of Nrdpl pathway components on the growth properties of cultured mouse and human mammary tumor cell lines will be examined using assays that measure proliferation, survival, motility and invasion. 3) The impact of Nrdpl on the growth of ErbB-induced mammary tumors in transgenic mouse models will be determined. These studies will assess whether overexpression of wild-type Nrdpl in the mouse mammary gland can suppress the latency, growth and metastasis of ErbB-induced mammary tumors, and whether overexpression of dominant-negative Nrdpl can induce mammary tumor formation or potentiate the latency or growth of ErbB-induced tumors. The results of these studies could implicate the Nrdpl pathway as a suppressor of tumor cell growth and progression, in turn suggesting that restoration or augmentation of pathway function in tumors could offer therapeutic benefit.