Convergence of CREB and MYC Pathways in Oncogenesis.

摘要 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导致 恶性的发展。定义启动和驱动肿瘤发生的分子事件，以及那些 都需要维持恶性状态，仍然是一项艰巨的任务。作为一个发现工具来审问 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，允许人们定义癌基因或肿瘤之间的功能相互作用 参与转录调控的抑制子和蛋白质。这项技术使人们能够整合基因 具有转录因子活性的表达数据，通过定义负责的上游转录调控因子 用来激活基因。在应用这项新技术时，我确定了 癌蛋白CRTC1/MAML2，由重复性t(11；19)(q21；p13.1)染色体产生 将CREB辅活化子CRTC1与缺口辅活化子MAML2和癌基因融合的易位 MYC。此外，我的初步研究强烈表明，CRTC1/MAML2癌蛋白劫持了Myc 推动细胞转化和肿瘤形成的网络。这些发现挑战了现有的范式，即 嵌合癌蛋白表现出仅与其组成的亲本分子有关的功能特征。 鉴于这些发现，我假设CREB和MYC转录因子网络在 致癌作用。使用经过验证的B细胞淋巴瘤模型的遗传学方法将用于测试这一点 假设，在那里我将评估CRTc1/MAML2与MAML2相互作用的相关性并定义机制(S MYC和CRTCs在驱动细胞转化、淋巴肿大和维持 恶性状态。

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.