Abl Kinases in growth factor signaling, motility, and invasion

Abl 激酶在生长因子信号传导、运动和侵袭中的作用

基本信息

批准号：
8123233
负责人：
RINA PLATTNER
金额：
$ 25.95万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2007-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8123233
关键词：
Adhesions Affect Animals Basement membrane Biochemical Biological Biological Assay Blood Blood Vessels Breast Cancer Cell Cancer Etiology Cancer cell line Cell Line Cell Proliferation Cells Cessation of life Chemotaxis Cultured Tumor Cells Cytoskeletal Modeling Data Development Distant Dominant-Negative Mutation Drug Combinations Epidermal Growth Factor Receptor Family Fatty acid glycerol esters Fibroblasts Goals Growth Factor Growth Factor Receptors Immigration Immune In Vitro Invaded Label Location MAP Kinase Gene Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Matrix Metalloproteinases Mediating Metalloproteases Metastatic Lesion Molecular Mus Neoplasm Metastasis Normal tissue morphology Organ PTK2 gene PTPN11 gene Pathway interactions Pharmaceutical Preparations Phosphotransferases Platelet-Derived Growth Factor Receptor Play Primary Neoplasm Process Proliferating Protein Tyrosine Kinase Proteins RNA Interference Regulation Resistance development Role Signal Transduction Site Solid Neoplasm Stream Tail Testing Translating Tumor Cell Invasion Veins base cell motility fluorescence imaging in vivo inhibitor/antagonist insight kinase inhibitor leukemia malignant breast neoplasm migration mortality prevent research study rho src-Family Kinases tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Growth factors modulate cell proliferation, migration, and survival. Precise regulation of these processes is critical as deregulated growth factor signaling increases cellular migration and drives tumor invasion and metastasis, the major cause of cancer-related deaths. Although Abl nonreceptor tyrosine kinases initiate leukemia development, their role in the development or progression of solid tumors has not been studied. Previously, we showed that Abl kinases are activated downstream of growth factor receptors via Src family kinases and PLC-yl, and influence growth factor-mediated cytoskeletal reorganization and migration in fibroblasts. Deregulation of growth factor receptors, Src kinases and PLC-yl in solid tumors, such as breast cancer, drives tumor invasion and metastasis. Our studies demonstrate that the Abl kinases are dramatically activated downstream of activated growth factor receptors and Src kinases in highly aggressive breast cancer cell lines, and promote breast cancer invasion. Based on these findings, the overall objective of this proposal is to characterize the conditions leading to Abl kinase activation in breast cancer, and to define invasion-promoting signaling cascades controlled by the Abl kinases. We hypothesize that Abl family kinases translate and direct growth factor receptor and Src kinase-mediated signals to influence breast cancer invasion and metastasis. Three Specific Aims are described to evaluate this hypothesis: 1) Determine the conditions that activate the Abl kinases in breast cancer; 2) Identify biological and molecular mechanisms by which Abl kinases promote breast cancer cell invasion; and 3) Determine whether activation of the Abl kinases promotes breast cancer metastasis, in vivo. To achieve our goal, we will combine biochemical, molecular, cellular, and whole animal approaches using: 1) primary breast tissue, breast cancer cell lines; RNAi, and inhibitors to identify mechanisms and conditions of Abl activation; 2) RNAi, chemotaxis, invasion, and zymography assays to identify mechanisms by which Abl kinases promote invasion; and 3) in vivo metastasis studies to assess whether activation of the Abl kinases promotes metastasis in immune- compromised mice. These data are likely to provide mechanistic insight into how abnormal regulation of the Abl kinases contributes to breast cancer progression, which may aid in the discovery of new drug combinations for preventing breast cancer metastasis and decreasing mortality.

描述（由申请人提供）：生长因子调节细胞增殖，迁移和生存。这些过程的精确调节至关重要，因为放松管制的生长因子信号传导增加了细胞迁移，并驱动肿瘤侵袭和转移，这是癌症相关死亡的主要原因。尽管ABL非受体酪氨酸激酶启动白血病的发育，但尚未研究它们在实体瘤的发展或进展中的作用。以前，我们表明ABL激酶是通过SRC家族激酶和PLC-Als激活生长因子受体的下游，并影响生长因子介导的成纤维细胞中的细胞骨架重组和迁移。乳腺癌（例如乳腺癌）中的生长因子受体，SRC激酶和PLC-yl的放松管制会驱动肿瘤侵袭和转移。我们的研究表明，在高度侵略性的乳腺癌细胞系中，ABL激酶在激活的生长因子受体和SRC激酶的下游显着激活，并促进乳腺癌侵袭。基于这些发现，该提案的总体目标是表征导致乳腺癌中ABL激酶激活的条件，并定义由ABL激酶控制的促进入侵信号传导级联。我们假设ABL家族激酶会翻译和直接生长因子受体和SRC激酶介导的信号，以影响乳腺癌的侵袭和转移。描述了三个特定的目的来评估这一假设：1）确定激活乳腺癌中ABL激酶的条件； 2）确定ABL激酶促进乳腺癌细胞侵袭的生物学和分子机制； 3）确定ABL激酶的激活是否在体内促进乳腺癌转移。为了实现我们的目标，我们将使用以下方式结合生化，分子，细胞和整个动物方法：1）原发性乳腺组织，乳腺癌细胞系； RNAi和抑制剂以鉴定ABL激活的机制和条件； 2）RNAi，趋化性，侵袭和Zymography测定法，以识别ABL激酶促进侵袭的机制； 3）体内转移研究以评估ABL激酶的激活是否促进了免疫受损小鼠的转移。这些数据可能会提供机械洞察力，了解ABL激酶的异常调节如何促进乳腺癌的进展，这可能有助于发现新药物组合，以预防乳腺癌转移和降低死亡率。