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: 8241509
• 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
• 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/8241509
• 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; Screening procedure; 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; tool; transcription factor; tumor; tumorigenesis

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.) PUBLIC HEALTH RELEVANCE: Cancers were the second leading cause of death in the United States in 2009 (559,888 deaths) with 28% due to lung and bronchus cancers and 8% due to leukemia and lymphoma; a subset of these primary lung and lymphoma tumors share a common t(11;19)(q21;p13.1) translocation that creates a chimeric CRTC1/MAML2 oncoprotein that we discovered coordinates the CRTC:CREB and MYC:MAX networks. Using a validated mouse model of human B cell lymphoma and leukemia, the goals of the proposed K99/R00 research are to study the role of the Myc:Max pathway in CRTC1/MAML2-mediated oncogenesis and critically assess the role of the CTRC:CREB pathway in cooperating with Myc to drive tumorigenesis, and in the maintenance of Myc- induced lymphoma. Since CREB regulates key aspects of cell survival and Myc is activated in up to 70% of all cancers, our discovery may provide the foundation for developing new agents that are broadly effective in cancer prevention and treatment.

描述(由申请人提供)：肿瘤发生是一个复杂的、多基因的过程，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。作为询问癌症相关转录网络的发现工具，我开发、测试和验证了一种基于哺乳动物细胞的创新筛选技术，该技术允许人们定义癌基因或肿瘤抑制基因与转录控制相关蛋白质之间的功能相互作用。这项技术通过定义负责基因激活的上游转录调控因子，使人们能够将基因表达数据与转录因子活性结合起来。在应用这项新技术的过程中，我发现了癌蛋白CRTC1/MAML2和癌基因myc之间的功能相互作用，CRTC1/MAML2是由反复的t(11；19)(q21；p13.1)染色体易位产生的，它将CREB共激活因子CRTC1与缺口辅助激活因子MAML2融合。此外，我的初步研究强烈表明，CRTC1/MAML2癌蛋白劫持了Myc网络，以驱动细胞转化和肿瘤发生。这些发现挑战了现有的范式，即嵌合癌蛋白显示出仅与其组成的亲本分子相关的功能特征。鉴于这些发现，我假设CREB和MYC转录因子网络在肿瘤发生中协同作用。我们将使用经过验证的B细胞淋巴瘤模型的遗传学方法来验证这一假说，在那里我将评估CRTc1/MAML2与MYC的相互作用的相关性并确定机制(S)，以及CRTCs在驱动细胞转化、淋巴癌发生和维持恶性状态中的作用。) 与公共卫生相关：2009年，癌症是美国第二大死因(559,888人死亡)，其中28%死于肺癌和支气管癌，8%死于白血病和淋巴瘤；这些原发肺部和淋巴瘤肿瘤中的一部分共享共同的t(11；19)(q21；p13.1)易位，产生了嵌合的CRTC1/MAML2癌蛋白，我们发现该蛋白协调CRTC：CREB和MYC：MAX网络。利用已证实的人类B细胞淋巴瘤和白血病的小鼠模型，拟议的K99/R00研究的目标是研究Myc：Max通路在CRTC1/MAML2介导的肿瘤发生中的作用，并关键地评估CTRC：CREB通路在与Myc协同驱动肿瘤形成和维持Myc诱导的淋巴瘤中的作用。由于CREB调控细胞存活的关键方面，而Myc在高达70%的癌症中被激活，我们的发现可能为开发在癌症预防和治疗中广泛有效的新药物提供基础。