Nrdp1 Protein Degradation Pathway in Mammary Tumor Progression

ErbB生长家族成员的异常过表达和伴随的激活 因子受体酪氨酸激酶在促进多种植物的生长和发育中起关键作用， 实体瘤类型。拟议研究的长期目标是了解 新的蛋白质降解途径调节ErbB诱导的肿瘤进展。中央 该途径的组分是称为Nrdpl的环指E3泛素连接酶，其介导了 ErbB受体的泛素化，从而促进其运输到降解的细胞 隔间指导这些研究的假设是Nrdpl蛋白降解途径 通过控制受体水平调节ErbB介导的细胞生长信号传导， 降解本供资期的两个首要目标是了解 Nrdpl活性调节的分子机制，并了解 ErbB受体诱导的乳腺肿瘤生长和进展的Nrdpl途径。这些 将通过三个具体目标来实现这些目标。1)Nrdpl的稳定性和活性的调节， 生长因子、信号激酶和去泛素化酶将用生化方法进行检测。 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 也要检查。2)Nrdpl通路组分的过表达或缺失对细胞凋亡的影响可能是一个潜在的因素。 将检测培养的小鼠和人乳腺肿瘤细胞系的生长特性 使用测量增殖、存活、运动和侵袭的分析。3)NRDPL的影响 将测定转基因小鼠模型中ErbB诱导的乳腺肿瘤的生长。 这些研究将评估野生型Nrdpl在小鼠乳腺中的过表达是否 能抑制ErbB诱导的乳腺肿瘤的潜伏期、生长和转移， 显性阴性Nrdpl的过度表达可诱导乳腺肿瘤形成或增强乳腺癌的发生。 ErbB诱导的肿瘤的潜伏期或生长。这些研究的结果可能暗示NRDPL 通路作为肿瘤细胞生长和进展的抑制因子，反过来表明， 增强肿瘤中的通路功能可以提供治疗益处。

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.