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MECHANISMS OF EPITHELIAL CELL TUMORIGENESIS IN THE MOUSE

小鼠上皮细胞肿瘤发生机制

基本信息

批准号：
7362427
负责人：
TERRY A VAN DYKE
金额：
$ 47.96万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7362427
关键词：
Adenocarcinoma Alleles Apoptosis Binding Biological CDK4 gene CDKN1A gene CDKN2A gene Cell Cycle Cell Cycle Progression Cell Proliferation Cells Characteristics Child Choroid Plexus Epithelium Complex Cyclin D1 Cyclin E Cyclin-Dependent Kinases DNA biosynthesis Defect Development Disruption Embryo Epithelial Epithelial Cells Epithelium Eukaryotic Cell Event Family Fibroblasts Figs - dietary Financial compensation Funding Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Growth Histone Deacetylase Human Inherited Malignant Neoplasms Mammals Mammary gland Mediating Modeling Mus Mutation Neoplasms Nucleosomes Nucleotide Biosynthesis Null Lymphocytes PTEN gene Pan Genus Pathway interactions Period Analysis Phase Phosphorylation Pituitary Gland Play Pre-Clinical Model Prostate Protein Family Proteins RBL2 gene Regulation Retinal Retinoblastoma Role SV40 T Antigens Simian virus 40 Specificity System TP53 gene Tissues Transgenic Mice Transgenic Organisms Tumor Suppression Tumor Suppressor Proteins antigen binding cell type gene repression human RBL2 protein human disease in vivo kinase inhibitor member mutant oncoprotein p21 osteosarcoma p107 protein response thyroid neoplasm tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The pRb tumor suppressor pathway is inactivated in most human cancers. In an attempt to model human cancers, we have inactivated this pathway tissue-specifically in the mouse by transgenic expression of T121, a truncated SV40 T antigen that binds and inactivates pRb and related proteins p107 and p130. Previously we showed that inactivation of the pRb proteins in choroid plexus epithelium (CPE) induces aberrant cell proliferation and p53-dependent apoptosis. Thus, pRb inactivation initiates tumorigenesis and sets up subsequent tumor dynamics. Aggressive tumor growth occurs upon p53 inactivation due in part to reduced apoptosis. During the last funding period, we analyzed the p53 tumor suppression pathway and have shown that p53 loss also facilitates progression by an as yet unknown mechanism. We have also extended these studies to examine additional epithelial cell types, including prostate (PE) and mammary (ME). In both cases inactivation of the pRb pathway leads to a similar induction of aberrant proliferation and apoptosis. However, while most apoptosis is mediated by p53 in CPE and ME it is mediated by PTEN in PE, indicating important mechanistic differences among cell types. In all cases, these responses predispose to adenocarcinoma, establishing tumor models characteristic of the human diseases. This proposal aims to integrate studies on cancer mechanisms in these epithelial cell types using genetically engineered mice (GEM). Our goal is to understand the mechanisms by which these events contribute to cancer development, thereby exploring the extent of cell specificity and characterizing the preclinical models we have established. The specific aims are to: (1) Define the p53-mediated apoptosis pathway(s) in tumor suppression. (2) Examine the mechanism(s) by which p53 and PTEN loss contribute to tumor progression in CPE, ME and PE. (3) Generate a pan-epithelial inducible system to inactivate the pRb pathway.

描述（由申请人提供）：pRb肿瘤抑制途径在大多数人类癌症中失活。在人类癌症模型的尝试中，我们通过转基因表达T121（一种截短的SV40 T抗原，可结合并灭活pRb和相关蛋白p107和p130），在小鼠中组织特异性地灭活了该途径。以前，我们表明，在脉络丛上皮细胞（CPE）的pRb蛋白的失活诱导异常细胞增殖和p53依赖性凋亡。因此，pRb失活启动肿瘤发生并建立随后的肿瘤动力学。侵袭性肿瘤生长发生在p53失活后，部分原因是细胞凋亡减少。在上一个资助期间，我们分析了p53肿瘤抑制途径，并表明p53丢失也通过一种未知的机制促进进展。我们还扩展了这些研究，以检查其他上皮细胞类型，包括前列腺（PE）和乳腺（ME）。在这两种情况下，pRb通路的失活导致异常增殖和凋亡的类似诱导。然而，虽然大多数细胞凋亡在CPE和ME中由p53介导，但在PE中由PTEN介导，这表明细胞类型之间存在重要的机制差异。在所有情况下，这些反应使腺癌易感，建立了人类疾病特征性的肿瘤模型。该提案旨在使用基因工程小鼠（GEM）整合这些上皮细胞类型中的癌症机制研究。我们的目标是了解这些事件促进癌症发展的机制，从而探索细胞特异性的程度并表征我们建立的临床前模型。具体目的是：（1）明确p53介导的肿瘤抑制凋亡途径。(2)检查p53和PTEN缺失导致CPE、ME和PE中肿瘤进展的机制。(3)产生泛上皮诱导系统以阻断pRb通路。