Defining a role for Hunk in oncogenic signaling

定义 Hunk 在致癌信号传导中的作用

基本信息

批准号：
7330026
负责人：
Elizabeth S. Yeh
金额：
$ 4.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7330026
关键词：
Address Affect Aggressive behavior Animals Biochemical Breast Cancer Etiology Carcinoma Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cellular biology Cessation of life Chronic Colon Cultured Cells Defect Development Doxycycline ERBB2 gene Elements Estrogens Exhibits Family Family member Feedback Gene Expression Profile Genetic Genus Cola Goals Growth Factor Health Homeostasis Homologous Gene Human Human Cloning In Vitro Laboratories Maintenance Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Modeling Molecular Mus Mutate Neoplasm Metastasis Numbers Oncogene Activation Oncogenes Oncogenic Ovary Pathway interactions Phosphotransferases Physiological Play Pregnancy Progesterone Protein Kinase Protein Kinase Inhibitors Protein Overexpression Protein-Serine-Threonine Kinases Role Role playing therapy Signal Pathway Signal Transduction Signaling Molecule Stress System Techniques Transgenic Organisms Transplantation Woman base cell growth improved in vivo insight lymph nodes malignant breast neoplasm member migration mouse model neoplastic neoplastic cell novel therapeutics protein kinase inhibitor research study response therapeutic target tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the mechanism by which Hunk acts intracellularly and determine the role of Hunk protein in tumorigenesis. The first aim of this proposal will address the participation of Hunk in Neu-driven mammary tumorigenesis. These experiments are important to determine the mechanisms by which Neu acts on tumor formation and maintenance. As Neu abberrations are observed in ~30% of human breast cancers, these studies will provide additional insight into the development of more effective treatments. This aim will be addressed using in vivo genetic approaches that employ a mouse model that encorporates an inducible system to drive Neu oncogenesis. These animals will then be crossed with Hunk deficient mice to generate Neu-inducible Hunk wildtype and deficient animals. These animals will be used for long-term chronic induction studies to identify a role for Hunk in tumor latency and multiplicity. In addition, short-term inductions will be performed to characterize the affect of Hunk on Neu-driven cell growth and proliferation. Finally this system will be used to address the role of Hunk in Neu-specific signaling. The second aim of this proposal will address the role of Hunk in PI3K-Akt signaling. As Hunk is a recently discovered protein kinase, little is known about its role as a signaling molecule. However, we have obtained preliminary evidence implicating Hunk in PI3K-Akt signaling. To address the second aim we will employ cell biology and biochemical techniques to establish the relationship between Hunk and PI3K-Akt signaling in the mammary gland. Specifically, we will determine whether a physical interaction exists between Hunk and Akt, whether Hunk is a substrate of Akt, and whether the activation of Akt through PI3K impinges on Hunk protein levels and/or activity. Experiments will also be performed to address the whether Hunk activity and/or levels affect the signaling capacity of Akt through PI3K. Finally, these experiments will include in vivo genetic studies to determine whether Hunk influences Akt-dependent tumorigenesis. The Akt pathway is mutated in many human cancers and, similar to Neu, there is frequently an increase in Akt activity in breast cancers. Consequently, the studies outlined in this proposal are important for understanding the molecular basis of breast cancer and how it can be more effectively treated. It is estimated that breast cancer will be the leading cause of cancer-related death in women in 2006. Several protein kinase inhibitors have been extremely effective for the treatment of human cancer. As such, characterization of novel therapeutic targets is an important element for improving human health.

描述（由申请人提供）：本提案的目的是了解Hunk在细胞内的作用机制并确定Hunk蛋白在肿瘤发生中的作用。该提案的首要目标是解决 Hunk 参与 Neu 驱动的乳腺肿瘤发生的问题。这些实验对于确定 Neu 对肿瘤形成和维持的作用机制非常重要。由于在约 30% 的人类乳腺癌中观察到 Neu 畸变，这些研究将为开发更有效的治疗方法提供更多见解。这一目标将通过体内遗传方法来实现，该方法采用小鼠模型，该模型包含诱导系统来驱动 Neu 肿瘤发生。然后将这些动物与 Hunk 缺陷小鼠杂交，产生 Neu 诱导的 Hunk 野生型和缺陷动物。这些动物将用于长期慢性诱导研究，以确定 Hunk 在肿瘤潜伏期和多重性中的作用。此外，还将进行短期诱导来表征 Hunk 对 Neu 驱动的细胞生长和增殖的影响。最后，该系统将用于解决 Hunk 在 Neu 特定信令中的作用。该提案的第二个目标是解决 Hunk 在 PI3K-Akt 信号传导中的作用。由于 Hunk 是一种最近发现的蛋白激酶，人们对其作为信号分子的作用知之甚少。然而，我们已经获得了 Hunk 参与 PI3K-Akt 信号转导的初步证据。为了实现第二个目标，我们将采用细胞生物学和生化技术来建立乳腺中 Hunk 和 PI3K-Akt 信号传导之间的关系。具体来说，我们将确定 Hunk 和 Akt 之间是否存在物理相互作用、Hunk 是否是 Akt 的底物以及通过 PI3K 激活 Akt 是否会影响 Hunk 蛋白水平和/或活性。还将进行实验来解决 Hunk 活动和/或水平是否影响 Akt 通过 PI3K 的信号传导能力。最后，这些实验将包括体内遗传学研究，以确定 Hunk 是否影响 Akt 依赖性肿瘤发生。 Akt 通路在许多人类癌症中发生突变，与 Neu 类似，乳腺癌中的 Akt 活性经常增加。因此，该提案中概述的研究对于了解乳腺癌的分子基础以及如何更有效地治疗乳腺癌非常重要。据估计，乳腺癌将成为2006年女性癌症相关死亡的主要原因。几种蛋白激酶抑制剂对于治疗人类癌症非常有效。因此，新治疗靶点的表征是改善人类健康的重要因素。