Molecular genetics of Mouse Lung Tumors

小鼠肺肿瘤的分子遗传学

基本信息

批准号：
7576931
负责人：
MING YOU
金额：
$ 24.82万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-01-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7576931
关键词：
3p21 3p21.3 A/J Mouse Adenocarcinoma Adenocarcinoma Cell Alleles Animals Apoptosis Apoptosis Inhibitor Binding Biological Assay Biological Models Cell Cycle Progression Cell Cycle Regulation Cell Line Cells Chemicals Chromosomes Colorectal Cancer Data Development Doxycycline Drug Delivery Systems Embryo Fibroblasts GTP Binding Gene Expression Genes HRAS gene Human Hypermethylation Knockout Mice Laboratories Loss of Heterozygosity Lung Lung Adenocarcinoma Lung Adenoma Lung Neoplasms Lymphomagenesis Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mammary Tumorigenesis Mediating Modeling Molecular Genetics Mouse Strains Mus Mutation Oncogenic Pathway interactions Proteins Proto-Oncogenes RAS genes Rattus Regulation Reporting Rodent Role Signal Pathway Staging Testing Thymic Lymphoma Tissues Transgenes Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Suppressor Gene Inactivation cancer cell cancer therapy cancer type carcinogenesis design loss of function lung carcinogenesis lung tumorigenesis mouse model novel overexpression promoter tumor tumor progression

3p21 3p21.3 A/J Mouse Adenocarcinoma Adenocarcinoma Cell Alleles Animals Apoptosis Apoptosis Inhibitor Binding Biological Assay Biological Models Cell Cycle Progression Cell Cycle Regulation Cell Line Cells Chemicals Chromosomes Colorectal Cancer Data Development Doxycycline Drug Delivery Systems Embryo Fibroblasts GTP Binding Gene Expression Genes HRAS gene Human Hypermethylation Knockout Mice Laboratories Loss of Heterozygosity Lung Lung Adenocarcinoma Lung Adenoma Lung Neoplasms Lymphomagenesis Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mammary Tumorigenesis Mediating Modeling Molecular Genetics Mouse Strains Mus Mutation Oncogenic Pathway interactions Proteins Proto-Oncogenes RAS genes Rattus Regulation Reporting Rodent Role Signal Pathway Staging Testing Thymic Lymphoma Tissues Transgenes Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Suppressor Gene Inactivation cancer cell cancer therapy cancer type carcinogenesis design loss of function lung carcinogenesis lung tumorigenesis mouse model novel overexpression promoter tumor tumor progression

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项目摘要

DESCRIPTION (provided by applicant): Recently, wild type ras genes have been shown to function as potent tumor suppressor genes. Both K-ras (hemizygous) and N-ras (homozygous) knockout mice are extremely prone to chemical induction of lung tumors and thymic lymphomas, respectively. Mice overexpressing wild type N-ras and rats overexpressing wild type K-ras and H-ras significantly inhibit thymic lymphomagenesis in mice and rat mammary tumorigenesis, respectively. These results indicate that wild type ras genes are tumor suppressors. This conclusion is further supported by observations of frequent loss of heterozygosity at the ras loci, which seem to fit the "two-hit" model of tumor suppressor gene inactivation in tumors. Another related tumor suppressor is RASSF1A that has been recently found to be the tumor suppressor residing on chromosome 3p21. RASSF1A is a Ras effector that binds to GTP-bound RAS. There are reports indicating that the occurrence of either K-ras mutations or RASSF1A inactivation activates the same signaling pathway in human tumors including lung. Accordingly, we hypothesize that activation of Ras-mediated pathways in mouse lung tumor progression occurs either by mutations of a Ras gene (oncogenic Ras and loss of wild type allele), or loss of function of the RASSF1A gene (LOH on Chr 3p21.3 and promoter hypermethylation), but infrequently by both, and the mechanisms used include the regulation of the ERK/AP-1 signaling pathways and activation of specific apoptosis inhibitors. Three specific aims are proposed to test our hypothesis: 1) to examine the mechanism of tumor suppressor function of wild type K-ras and RASSF1A using lung cancer cells conditionally expressing these genes and mouse embryonic fibroblasts lacking these genes; 2) to determine if K-ras alterations and RASSF1A hypermethylation occur independently in mouse lung tumorigenesis; and 3) to determine effect of RASSF1A deficiency and regulated expression of this gene on mouse lung tumor progression in mice. We propose that wild type K-ras and RASSF1A are related novel tumor suppressors of lung cancer as well as other cancer types. There is evidence to indicate that there are tissue-specific interactions between the wild type K-ras and RASSF1A in their roles as tumor suppressors. Understanding the mechanism(s) underlying these two newly discovered tumor suppressors would have immediate and important implications for our understanding of carcinogenesis and potentially provides better drug targets for cancer therapy.

描述（由申请人提供）：最近，野生型Ras基因已被证明充当有效的肿瘤抑制基因。 K-RAS（Hemizygous）和N-RAS（纯合）敲除小鼠分别非常容易诱导肺部肿瘤和胸腺淋巴瘤。过表达野生型N-RAS和过表达野生型K-RAS和H-RAS的小鼠分别显着抑制小鼠和大鼠乳腺肿瘤发生的胸腺淋巴瘤发生。这些结果表明野生型Ras基因是肿瘤抑制子。通过观察到RAS基因座的杂合性频繁丧失的观察，这似乎是符合肿瘤抑制肿瘤基因失活的“两击”模型的进一步支持。另一个相关的肿瘤抑制剂是RASSF1A，最近被发现是驻留在3p21染色体上的肿瘤抑制剂。 RASSF1A是与GTP结合的RA结合的RAS效应器。有报道表明，K-RAS突变或RASSF1A失活的发生会激活包括肺在内的人类肿瘤中相同的信号通路。 Accordingly, we hypothesize that activation of Ras-mediated pathways in mouse lung tumor progression occurs either by mutations of a Ras gene (oncogenic Ras and loss of wild type allele), or loss of function of the RASSF1A gene (LOH on Chr 3p21.3 and promoter hypermethylation), but infrequently by both, and the mechanisms used include the regulation of the ERK/AP-1 signaling pathways和特定凋亡抑制剂的激活。提出了三个具体目的来检验我们的假设：1）使用有条件表达这些基因的肺癌细胞和缺乏这些基因的小鼠胚胎成纤维细胞来检查野生型K-RAS和RASSF1A的肿瘤抑制器功能的机制； 2）确定在小鼠肺肿瘤发生中是否独立发生K-RAS改变和RASSF1A高甲基化； 3）确定RASSF1A缺乏症和该基因的调节表达对小鼠肺肿瘤进展的影响。我们建议野生型K-RAS和RASSF1A是相关的肺癌和其他癌症类型的新型肿瘤抑制剂。有证据表明，野生型K-RAS和RASSF1A之间在其作为肿瘤抑制器的作用中存在组织特异性相互作用。了解这两个新发现的肿瘤抑制剂的基础机制将对我们对癌变的理解具有直接而重要的含义，并有可能为癌症治疗提供更好的药物靶标。