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Syk and associated proteins in breast cancer

乳腺癌中的 Syk 和相关蛋白

基本信息

批准号：
7326857
负责人：
ROBERT L GEAHLEN
金额：
$ 25.3万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-06 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7326857
关键词：
Antigens Arts Benign Binding Biochemical Genetics Breast Breast Cancer Cell Carcinoma Cell Adhesion Cell Communication Cell Death Cell Survival Cell physiology Cell-Cell Adhesion Cells Critical Pathways Development Disruption Enzymes Epigenetic Process Epithelial Cells Epithelium Evaluation Extracellular Matrix Genetic Growth Health Immune response Immune system Invasive Light Malignant - descriptor Measures Mediating Methodology Microscopic Neoplasm Metastasis Oncogene Activation Oncogene Proteins Oncogenes Pathway interactions Personal Satisfaction Phenotype Phosphotyrosine Play Predisposition Process Property Protein Tyrosine Kinase Proteins Proteome Regulation Research Role Signal Pathway Signal Transduction Therapeutic Thinking Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor Suppressor Proteins Tumor-Suppressor Gene Inactivation United States Woman base cancer cell cell growth cell motility human TNF protein malignant breast neoplasm malignant phenotype neoplastic cell novel novel therapeutics protein function protein protein interaction response src Homology Region 2 Domain therapeutic target transcription factor tumor progression tumorigenesis tumorigenic

项目摘要

In breast cancer, tumorigenesis occurs through an accumulation of genetic and epigenetic changes in epithelial cells involving both the activation of oncogenes and the inactivation of tumor suppressor genes. The Syk protein-tyrosine kinase, known best for its roles in the immune system, has recently been identified as a tumor suppressor in breast cancer; its expression being inversely correlated with malignant cell growth and metastasis. This is an unusual property for a tyrosine kinase, enzymes more typically found as the products of oncogenes. Thus, an understanding of how Syk functions to suppress the malignant phenotype of breast cancer cells is of considerable importance to our understanding of the critical pathways involved in growth control in breast epithelial cells and to the identification of possible, novel therapeutic targets. Preliminary studies have led to the hypothesis that Syk regulates two important aspects of of epithelial cell function: 1) cellular responses to tumor necrosis factor (TNF), a factor that regulates cell death/cell survival decisions and 2) cell adhesion and motility. These hypotheses are based on the identification of Syk- interacting proteins that participate in each of these pathways. The research proposed in this project will 1) characterize the physical and functional interactions between Syk and components of the TNF-signaling pathway with an emphasis on the characterization of a novel Syk-interacting protein thought to participate in this pathway; 2) characterize the critical structural features and mechanisms by which Syk, through its interacting partners, regulates cell adhesion and motility; and 3) characterize through phosphoproteomics studies the substrates and binding partners important for Syk's regulatory functions in breast epithelial cells. Methodologies to be employed include 1) genetic, biochemical and microscopic evaluations of protein- protein interactions and the consequences of their disruption and 2) state-of-the-art analyses of the phosphoproteome of Syk-expressing cells.

在乳腺癌中，肿瘤的发生是通过积累遗传和表观遗传变化来实现的。涉及癌基因激活和抑癌基因失活的上皮细胞。 Syk蛋白酪氨酸激酶，以其在免疫系统中的作用而闻名，最近被发现。作为乳腺癌中的肿瘤抑制因子；其表达与恶性细胞生长呈负相关和转移。对于酪氨酸酶来说，这是一种不寻常的特性，这种酶通常被发现为致癌基因产物。因此，了解Syk如何发挥抑制恶性表型的作用对于我们理解乳腺癌细胞所涉及的关键途径是相当重要的。乳房上皮细胞的生长控制和确定可能的、新的治疗靶点。初步研究得出这样的假设，即Syk调节上皮细胞的两个重要方面功能：1)细胞对肿瘤坏死因子的反应，肿瘤坏死因子是一种调节细胞死亡/细胞存活的因子决定和2)细胞粘附性和运动性。这些假说是基于对Syk的识别-- 参与这些途径的相互作用的蛋白质。本项目中提出的研究将1) 描述Syk和肿瘤坏死因子信号转导组件之间的物理和功能相互作用途径，重点是一种新的Syk相互作用蛋白的特征 2)描述了Syk的关键结构特征和机制，通过其相互作用的伙伴，调节细胞的黏附和运动；以及3)通过磷酸蛋白质组学表征研究Syk在乳腺上皮细胞中调节功能的重要底物和结合伙伴。将采用的方法包括1)蛋白质的遗传、生化和显微评估- 蛋白质相互作用及其破坏的后果和2)最先进的分析表达Syk的细胞的磷酸蛋白质组。