Convergence of CREB and MYC Pathways in Oncogenesis.

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。定义启动和驱动肿瘤发生的分子事件，以及那些维持恶性状态所必需的分子事件，仍然是一项艰巨的任务。作为研究与癌症相关的转录网络的发现工具，我已经开发、测试和验证了一种创新的基于哺乳动物细胞的筛选技术，该技术允许人们定义癌基因或肿瘤抑制因子与转录控制相关的蛋白质之间的功能相互作用。通过定义负责基因激活的上游转录调控因子，该技术允许人们将基因表达数据与转录因子活性结合起来。在应用这项新技术时，我发现了癌蛋白CRTC1/MAML2和癌基因MYC之间的功能相互作用，这是由复发性t(11;19)（q21;p13.1）染色体易位产生的，该易位融合了CREB共激活子CRTC1和NOTCH共激活子MAML2。此外，我的初步研究强烈表明，CRTC1/MAML2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，即嵌合癌蛋白仅显示与其组成母体分子相关的功能特征。鉴于这些发现，我假设CREB和MYC转录因子网络在肿瘤发生中相互合作。使用经过验证的B细胞淋巴瘤模型的遗传方法将用于验证这一假设，其中我将评估CRTC1/MAML2与MYC相互作用的相关性并定义其机制，以及CRTCs在驱动细胞转化、淋巴瘤发生和恶性状态维持中的作用。

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.)