Cancer and Gene Regulation by the pRB/E2F Pathway

pRB/E2F 途径的癌症和基因调控

基本信息

批准号：
8133470
负责人：
Jacqueline A. Lees
金额：
$ 34.04万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133470
关键词：
Address Affect Apoptosis Apoptotic Arts Attention Binding Biochemistry Bioinformatics Biological Assay Biology CCR Caenorhabditis elegans Cell Cycle Cell Cycle Arrest Cell Proliferation Cell Survival Cells Collaborations Complement Complex Core Facility Data Development E2F1 gene Event Faculty Family Family member Floor Funding Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Goals Human Individual Joints Libraries Link Logic Lung Neoplasms Malignant Neoplasms MicroRNAs Mus Mutant Strains Mice Normal Cell Oncogenes Oncogenic Participant Pathway interactions Pattern Period Analysis Phosphotransferases Play Preparation Principal Investigator Process Property Proteins RNA Interference Reagent Recruitment Activity Regulation Repression Research Retinoblastoma Protein Role Science Signal Transduction Small Interfering RNA Small RNA Source Stimulus Students System TP53 gene Technical Expertise Technology Testing Transcriptional Activation Tumor Cell Line Tumor Suppressor Proteins anticancer research base c-myc Genes chromatin immunoprecipitation drug development embryonic stem cell gene repression genome wide association study human DICER1 protein in vivo meetings member metaplastic cell transformation mouse model mutant mouse model neoplastic cell novel programs research study response small hairpin RNA success tool tumor tumorigenic vector

项目摘要

Alterations in gene regulation play a key role in the tumorigenic process. Our research centers on two tumor suppressor pathways, p16lnk4a-cycD/cdk4-pRB-E2F and p19Art-mdm2-p53, that control the expression of genes required for cellular proliferation or the tumor surveillance response respectively. We have established a direct link between the pRB/E2F and An7p53 pathways in vivo (Aslanian et al., 2004): specific E2F family members contribute to either the transcriptional repression of Arf in normal cells (via E2F3B) or the transcriptional activation of /A/fin tumor cells (via the activating E2Fs). Experiments in this proposal will use a combination of mouse models (and the resulting cell lines and tumors) and RNAi technology to understand the role of the pRB/E2F pathway in the control of Arf transcription and cellular proliferation. They will also establish how the pRB pathway and cellular transformation influence miRNA regulation and function. There are four goals: (1) To identify the E2F3B represser complex; (2) To understand how the activating E2Fs induce Arf and other "tumor-specific" E2F-responsive genes; (3) To test the requirement for activating E2Fs in the regulation of normal and tumor cells; and (4) To screen for pathways that synergize with pRB in the control of cell proliferation and survival.

基因调节的改变在致瘤过程中起关键作用。我们的研究集中于两个肿瘤抑制器途径，P16LNK4A-CYCD/CDK4-PRB-E2F和P19ART-MDM2-P53，控制着控制的表达细胞增殖或肿瘤监测反应所需的基因。我们有在体内建立了PRB/E2F和AN7P53途径之间的直接联系（Aslanian等，2004）：特定 E2F家庭成员在正常细胞（通过E2F3B）或 /A /FIN肿瘤细胞的转录激活（通过激活E2F）。该提案中的实验将使用小鼠模型（以及所得的细胞系和肿瘤）和RNAi技术的组合了解PRB/E2F途径在控制ARF转录和细胞增殖中的作用。他们还将确定PRB途径和细胞转化如何影响miRNA调控和功能。有四个目标：（1）识别E2F3B阻遏物复合体；（2）了解如何激活E2F会诱导ARF和其他“肿瘤特异性” E2F响应基因；（3）测试要求在正常细胞和肿瘤细胞的调节中激活E2F；（4）筛选协同的途径 PRB控制细胞增殖和存活。