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.

摘要 肿瘤发生是一个复杂的多基因过程，导致细胞转化，并最终导致肿瘤的发生。 恶性肿瘤的发展。定义启动和驱动肿瘤发生的分子事件，以及那些 要保持恶性状态，仍然是一项艰巨的任务。作为一种发现工具来审问 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 基于细胞的筛选技术，允许定义癌基因或肿瘤之间的功能相互作用 抑制子和涉及转录控制的蛋白质。这项技术允许人们整合基因 表达数据与转录因子活性，通过定义上游转录调控负责 基因激活。在应用这项新技术时，我发现了 癌蛋白CRTC 1/MAML 2，由复发性t（11;19）（q21;p13.1）染色体产生 将CREB共激活因子CRTC 1与NOTCH共激活因子MAML 2融合的易位，以及癌基因 MYC。此外，我的初步研究强烈表明，CRTC 1/MAML 2癌蛋白劫持了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范式， 嵌合癌蛋白显示仅与其组成亲本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， 肿瘤发生将使用经验证的B细胞淋巴瘤模型的遗传方法来检验这一点 假设，其中我将评估相关性并定义CRTC 1/MAML 2与 MYC和CRTCs在驱动细胞转化、淋巴瘤发生和维持细胞增殖中的作用 恶性状态