Cell Autonomy and Tumor Suppression by CDK inhibitors

CDK 抑制剂的细胞自主性和肿瘤抑制

基本信息

批准号：
7363639
负责人：
Matthew L Fero
金额：
$ 34.08万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7363639
关键词：
Address Adhesions Alleles Animals Automobile Driving B-Lymphocytes Biochemical Biological Assay Biological Models Breeding Carcinogens Cell Count Cell Cycle Cell Cycle Proteins Cells Cellularity Cultured Cells Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cyclins Data Development Disruption Epithelial Exposure to Female infertility Gene Expression Gene Mutation Genes Genetic Glypican Gonadotropins Growth Growth Factor Growth Inhibitors Haploidy Hematopoietic Hyperplasia Induced Mutation Infertility Knock-out Lead Lymphocyte Lymphoma Lymphomagenesis Malignant Neoplasms Measures Mediating Modeling Mus Mutation Neoplasms Nitrosourea Compounds Normal Cell Oncogenes Pathologic Pattern Phenotype Pituitary Gland Pituitary Gland Adenoma Pituitary Neoplasms Population Pro-Opiomelanocortin Production Rate Recovery Research Personnel Role Serum Signal Transduction Splenocyte T-Cell Lymphoma T-Lymphocyte Tamoxifen Testing Thymic epithelial cell Thymus Gland Time Tissues Transgenes Transgenic Organisms Tumor Biology Tumor Promotion Tumor Suppression Tumor Suppressor Genes Virus Work adenoma angiogenesis c-Myc Staining Method carcinogenesis cdc Genes cell growth chemical carcinogen extracellular inhibitor/antagonist knockout animal mortality mouse model mutant neoplastic nerve supply novel p27 Cell Cycle Protein p27 Enzyme Inhibitor paracrine pars intermedia programs protein function size thymocyte tumor tumor growth tumorigenesis vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Models of tumor suppression by cell cycle growth inhibitors commonly assume that the critical inhibitory activity is intrinsic to the tumor clone. The recent discovery of tumor suppressor genes which are incapable of fully suppressing neoplastic growth with loss of only a single gene copy (i.e. haploid insufficient tumor suppression) in mouse models raises the possibility of alternative, non cell-autonomous mechanisms of tumor suppression. For example, loss of cell cycle inhibitor expression in cells extrinsic to the neoplastic clone may enhance cell growth by signals mediated through extracellular contact, paracrine factors, or angiogenesis. This project will further our understanding of the mechanism of tumor suppression by the CDK inhibitor p27Kipl and several interacting molecules. The studies will create targeted mutations in the mouse in which p27 is either deleted or activated in specific tissues. These novel gene mutations will then be combined with well defined murine models of induced carcinogenesis and gene expression analysis to define the mechanism of tumor suppression of p27 and its biochemical effects in tumorigenesis. By developing mice which harbor cell cycle gene mutations confined to the pituitary or thymus it will be determined whether the p27Kip 1 can induce adenomas and lymphomas in these tissues in a cell autonomous fashion, that is independent of the influence of factors from surrounding cells or tissues. In each model system the mechanism of tumor suppression by p27 will be further defined and the patterns of altered gene expression and cell cycle protein function will be characterized. In order to treat cancer with inhibitors of cyclin dependent kinases it is essential to identify the appropriate target cell population. Inhibition of tumorigenesis by targeting growth of normal cell populations may have the advantage of being more predictable and less prone to escape by mutations in the tumor clone.

描述（由申请人提供）：细胞周期生长抑制剂抑制肿瘤模型通常假定临界抑制活性是肿瘤克隆的固有的。在小鼠模型中，几乎无法完全抑制肿瘤生长的肿瘤抑制基因（即单倍体不足的肿瘤抑制作用）无法完全抑制肿瘤生长。例如，细胞周期抑制剂表达在细胞外的肿瘤克隆中的表达可能会通过通过细胞外接触，旁分泌因子或血管生成介导的信号来增强细胞生长。该项目将进一步理解CDK抑制剂P27KIPL和几种相互作用的分子的肿瘤抑制机制。研究将在小鼠中产生靶向突变，其中p27在特定组织中被删除或激活。然后，这些新型基因突变将与明确定义的诱发癌变和基因表达分析的鼠模型结合使用，以定义p27肿瘤抑制的机制及其在肿瘤发生中的生化作用。通过开发携带细胞周期基因突变的小鼠，局限于垂体或胸腺，可以确定P27KIP 1是否可以以细胞自主的方式诱导这些组织中的腺瘤和淋巴瘤，这与周围细胞或组织的因素的影响无关。在每个模型系统中，将进一步定义p27抑制肿瘤的机制，并且将表征改变基因表达和细胞周期蛋白功能的模式。为了用细胞周期蛋白依赖性激酶的抑制剂治疗癌症，必须鉴定适当的靶细胞群。通过靶向正常细胞种群的生长来抑制肿瘤发生可能具有更容易预测的优势，并且不容易被肿瘤克隆中的突变逃脱。