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: 8928274
• 负责人: Antonio Luigi Amelio
• 金额: $ 24.15万
• 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/8928274
• 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; 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; 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