Mechanism and Impact of an Interaction Between Keratin 19 and a Regulator of Gene Expression

项目总结 中间丝蛋白构成了细胞骨架蛋白的最大家族，并且发生了突变或改变 中间丝蛋白的表达与人类80多种疾病有关或显著相关。 中间纤维相关疾病的一个关键特征是改变基因的表达谱， 直接导致疾病进展。一种这样的疾病类型是上皮癌，角蛋白 中间丝蛋白被广泛用作人类患者的诊断和预后标志物，以及 在动物模型中，选择角蛋白促进肿瘤进展。在乳腺癌中，角蛋白19(K19)是 最可靠和被广泛研究的诊断标记物，其高表达与更差相关 患者预后。然而，该生物标记物在肿瘤发生发展中的具体作用尚不清楚。 基于我们在人类乳腺癌细胞中的初步数据和之前对皮肤中一种相关角蛋白的研究 我们认为K19调控肿瘤转移相关基因的表达，并促进 通过与hnRNP K直接相互作用的转移细胞行为hnRNP K是一种RNA结合蛋白，它 调节一系列促肿瘤基因的表达，并在体内积累时促进转移 细胞质。我们推测，K19纤维是hnRNP K到后修复的细胞质支架。 转录调控促进侵袭细胞行为的基因，从而导致肿瘤转移。这 该提案旨在揭示K19和hnRNP K如何相互作用的机制细节(目标1)，以及 确定K19-hnRNP K合作在分子和细胞水平以及体内的影响 它们在肿瘤转移中的表达意义(目标2)。达到上述目标将确定 肿瘤标记物在转移中的作用，决定表达的调控机制 并揭示了hnRNP K在细胞质中的积累是如何促进 转移。这一提议也有可能确定一种新的中间纤维调节剂 组织。最终，所获得的知识可以帮助开发抗击癌症的新治疗策略。 作为更好地理解中间丝基因存在的无数疾病的蓝图 突变的或表现出改变的表情的。

PROJECT SUMMARY Intermediate filament proteins make up the largest family of cytoskeletal proteins, and mutation or altered expression of intermediate filament proteins cause or significantly correlate with more than 80 human diseases. One key feature of the intermediate filament-associated diseases is altered expression profiles of genes that directly contribute to disease progression. One such disease type is epithelial cancers, where keratin intermediate filament proteins are widely used as diagnostic and prognostic markers for human patients, and select keratins promote tumor progression in animal models. In breast cancer, Keratin 19 (K19) is one of the most reliable and extensively studied diagnostic markers, and its higher expression correlates with worse patient prognosis. However, the specific impact of this biomarker in the tumor development remains unknown. Based on our preliminary data in human breast cancer cells and previous work on a related keratin in skin cancer cells, we propose that K19 regulates the expression of metastasis-related genes and promote metastatic cell behaviors through a direct interaction with hnRNP K. hnRNP K is a RNA-binding protein that regulates the expression of a host of pro-tumorigenic genes and promotes metastasis when accumulated in the cytoplasm. We hypothesize that K19 filaments function as cytoplasmic scaffolds for hnRNP K to post- transcriptionally regulate genes that promote invasive cell behaviors that lead to tumor metastasis. This proposal is aimed at uncovering the mechanistic details of how K19 and hnRNP K interact (Aim 1), and identifying the impact of K19-hnRNP K cooperation at the molecular and cellular levels, as well as the in vivo significance of their expression in tumor metastasis (Aim 2). Meeting the above aims will identify the contribution of a tumor marker towards metastasis, determine the regulatory mechanism governing expression of metastasis-associated genes, and reveal how the cytoplasmic accumulation of hnRNP K promotes metastasis. This proposal also has the potential to identify a novel regulator of intermediate filament organization. Ultimately, the knowledge gained can help develop novel therapeutic strategies to combat cancer and serve as a blueprint to better understand a myriad of diseases where intermediate filament genes are mutated or show altered expression.