权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Convergence of CREB and MYC Pathways in Oncogenesis.

CREB 和 MYC 通路在肿瘤发生中的融合。

基本信息

批准号：
8544427
负责人：
Antonio Luigi Amelio
金额：
$ 14.72万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-12 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8544427
关键词：
Acute Myelocytic Leukemia Asses Automobile Driving B-Cell Development B-Cell Lymphomas B-Lymphocytes Binding Breast Bronchi C-terminal CREB1 gene Cause of Death Cell Survival Cell division Cervix Uteri Cessation of life Characteristics Chromosomal translocation Complex Cutaneous Cyclic AMP Response Element Data Development Dimerization E-Box Elements Event Family member Foundations Gene Activation Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Human Indium Insulin Receptor Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Link Lung Lung Adenocarcinoma Lung Lymphoma Lymphoma Lymphomagenesis MLL/ELL Maintenance Malignant Neoplasms Mammalian Cell Mediating Mentors Messenger RNA Metastatic Carcinoma Modeling Molecular Mus N-terminal New Agents Oncogene Proteins Oncogenes Parents Pathway interactions Premalignant Process Promoter Regions Prostate Adenocarcinoma Proto-Oncogene Proteins c-myc Recurrence Regulation Research Research Project Grants Response Elements Role Salivary Glands Signal Transduction Site Sweat Glands T-Cell Lymphoma Technology Testing Thyroid Gland Training Transcription Coactivator Transcriptional Regulation Transgenic Mice Tumor Suppressor Proteins United States autocrine base cancer prevention cancer therapy cell growth cell transformation chromatin immunoprecipitation in vivo innovation leukemia leukemia/lymphoma lung tumorigenesis malignant state metaplastic cell transformation mouse model new technology promoter receptor screening tool transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Tumorigenesis is a complex, multigenic process that leads to cell transformation and ultimately to the development of malignancy. Defining the molecular events that initiate and drive oncogenesis, and those that are required to maintain the malignant state, remain a formidable task. As a discovery tool to interrogate transcriptional networks involved in cancer, I have developed, tested and validated an innovative mammalian cell-based screening technology that allows one to define functional interactions between oncogenes or tumor suppressors and proteins implicated in transcriptional control. This technology allows one to integrate gene expression data with transcription factor activity, by defining the upstream transcriptional regulators responsible for gene activation. In applying this new technology, I identified a functional interaction between the oncoprotein CRTC1/MAML2, which is generated by the recurrent t(11;19)(q21;p13.1) chromosomal translocation that fuses the CREB coactivator CRTC1 to the NOTCH coactivator MAML2, and the oncogene MYC. Further, my Preliminary Studies strongly suggest that the CRTC1/MAML2 oncoprotein hijacks the Myc network to drive cell transformation and tumorigenesis. These findings challenge the existing paradigm that chimeric oncoproteins display functional characteristics related solely to their constituent parent molecules. Given these findings, I hypothesize that CREB and MYC transcription factor networks cooperate in oncogenesis. Genetic approaches using validated models of B cell lymphoma will be used to test this hypothesis, where I will assess the relevance and define the mechanism(s) of CRTC1/MAML2 interactions with MYC and the role of CRTCs in driving cell transformation, lymphomagenesis, and the maintenance of the malignant state.)

描述（由申请人提供）：肿瘤发生是一个复杂的多基因过程，导致细胞转化并最终发展为恶性肿瘤。确定启动和驱动肿瘤发生的分子事件，以及维持恶性状态所需的分子事件，仍然是一项艰巨的任务。作为一种发现工具，询问参与癌症的转录网络，我已经开发，测试和验证了一种创新的哺乳动物细胞为基础的筛选技术，允许一个定义的癌基因或肿瘤抑制因子和蛋白质之间的功能相互作用，涉及转录控制。该技术允许通过定义负责基因激活的上游转录调节因子来整合基因表达数据与转录因子活性。在应用这项新技术时，我确定了癌蛋白CRTC 1/MAML 2和癌基因MYC之间的功能性相互作用，该癌蛋白CRTC 1/MAML 2是由复发性t（11;19）（q21;p13.1）染色体易位产生的，该易位将CREB共激活因子CRTC 1融合到NOTCH共激活因子MAML 2。此外，我的初步研究强烈表明，CRTC 1/MAML 2癌蛋白劫持Myc网络来驱动细胞转化和肿瘤发生。这些发现挑战了现有的模式，即嵌合癌蛋白显示功能特性仅与其组成的亲本分子。鉴于这些发现，我假设CREB和MYC转录因子网络在肿瘤发生中合作。使用经验证的B细胞淋巴瘤模型的遗传方法将用于检验这一假设，其中我将评估相关性并定义CRTC 1/MAML 2与MYC相互作用的机制以及CRTCs在驱动细胞转化、淋巴瘤发生和维持恶性状态中的作用。）