Convergence of CREB and MYC Pathways in Oncogenesis.

CREB ​​和 MYC 通路在肿瘤发生中的融合。

• 批准号: 8930922
• 负责人: Antonio Luigi Amelio
• 金额: $ 24.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930922
• 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 Transcription; Genetic study; 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; genetic approach; 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

ABSTRACT 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.

抽象的 肿瘤发生是一个复杂的多基因过程，可导致细胞转化，最终导致 恶性肿瘤的发展。定义引发和驱动肿瘤发生的分子事件，以及 需要维持恶性状态，仍然是一项艰巨的任务。作为询问的发现工具 涉及癌症的转录网络，我已经开发，测试和验证了创新的哺乳动物 基于细胞的筛选技术，允许人们定义癌基因或肿瘤之间的功能相互作用 抑制剂和蛋白质与转录控制有关。这项技术允许人们整合基因 具有转录因子活动的表达数据，通过定义负责的上游转录调节器 用于基因激活。在应用这项新技术时，我确定了 癌蛋白CRTC1/MAML2，由复发t（11; 19）（q21; p13.1）生成 将CREB共激活因子CRTC1融合到Notch共激活器MAML2的易位和癌基因 妈妈。此外，我的初步研究强烈表明CRTC1/MAML2癌蛋白劫持了MYC 驱动细胞转化和肿瘤发生的网络。这些发现挑战了现有的范式 嵌合癌蛋白显示出与其成分母体分子相关的功能特征。 鉴于这些发现，我假设CREB和MYC转录因子网络合作 肿瘤发生。使用经过验证的B细胞淋巴瘤模型的遗传方法将用于测试 假设，我将评估相关性并定义与CRTC1/MAML2相互作用的机制 MYC和CRTC在驱动细胞转化，淋巴作用和维持中的作用 恶性国家。