Decoding the Translational Program Underlying the Oncogenic Stress Response

解码致癌应激反应背后的转化程序

• 批准号: 8783501
• 负责人: Crystal S Conn
• 金额: $ 1.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783501
• 关键词: 5' Untranslated Regions; Address; Affinity; Biological Markers; Buffers; Cancer Control; Cancer Patient; Candidate Disease Gene; Cell Survival; Cells; Cellular Stress; Cellular Stress Response; Cessation of life; Clinical; DNA Damage; Data; Development; Employee Strikes; Eukaryotic Initiation Factors; Event; Financial compensation; Foundations; Gene Expression; Genes; Genetic; Genetic Translation; Human; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Mediating; Messenger RNA; Metabolic; Molecular; Molecular Genetics; Mus; Non-Small-Cell Lung Carcinoma; Normal Cell; Nucleotides; Oncogenes; Oncogenic; Oxidative Stress; Pathway interactions; Patients; Phenotype; Physiology; Process; RNA Cap-Binding Proteins; Reactive Oxygen Species; Regimen; Regulation; Regulatory Element; Research; Resistance; Resources; Role; Sampling; Stress; Technology; Testing; Therapeutic; Therapeutic Agents; Transcript; Transgenic Mice; Translating; Translations; Validation; base; biological adaptation to stress; cancer cell; cancer type; cell transformation; cellular development; design; dosage; genome-wide; in vivo; loss of function; mammalian genome; metaplastic cell transformation; mouse model; neoplastic cell; novel; novel therapeutics; outcome forecast; overexpression; programs; public health relevance; response; small molecule; stress tolerance; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): A fundamental response to oncogenic transformation is enhanced cellular stress (e.g. oxidative, metabolic, and DNA damage), which is a hallmark of cancer cells. These common stress phenotypes must be tolerated by cancer cells through stress support pathways. Moreover, adaptation to stress is required for cancer cell survival, and consequently they may become dependent on stress response pathways that do not ordinarily perform such a vital function in normal cells. Thus, targeting these associated vulnerabilities to stress adaptation are clearly vital and offer a tremendous window of opportunity for a synthetic lethal interaction that may elicit selective death of cancer cells. Despite the tremendous importance of the stress phenotype of cancer cells, there is a large gap in our understanding of the genetic basis for how stress tolerance is maintained in transformed cells, thereby limiting our ability to design rational therapeutic agents. Our preliminary findings reveal that the major cap-binding protein eIF4E is a central integrator of the translation program for the adaption of cancer cells to oncogenic stress. By generating the first genetic loss-of-function mouse model for eIF4E, we have unexpectedly discovered that a 50% reduction in eIF4E has no effect on normal development, but strikingly is limiting for oncogenic transformation. Utilizing unbiased genome-wide translational profiling, we find that eIF4E selects for the translation of specific subsets of mRNAs involved in cellular stress response pathways, including oxidative stress. This proposal aims to undertake a multifaceted approach to delineate the contribution of eIF4E- dependent control of reactive oxygen species in tumor development and maintenance of non-small cell lung carcinoma in vivo, and explore the therapeutic potential of inhibiting eIF4E in combination with small molecules that induce oxidative stress. Furthermore, our finding that eIF4E is rate limiting for only a subset of mRNAs that regulate cellular stress response pathways is striking, and suggests that a novel regulatory program promotes selectivity for cancer cell survival. We aim to define the underlying molecular mechanisms by which an identified novel cis-acting regulatory motif, in the 5'UTR of select mRNAs, confers eIF4E sensitivity. Collectively, our data demonstrate that eIF4E-dependent control of these stress response pathways is critical for oncogenic transformation and tumor cell survival. These findings lay the foundation for this proposal, which seeks to open a new portal into our understanding of the translation program that maintains the adaptation of cancer cells to stress and develop a novel therapeutic regimen to target this vulnerability of transformed cells.

描述（由申请人提供）：对致癌转化的基本反应是增强细胞应激（例如氧化，代谢和DNA损伤），这是癌细胞的标志。这些常见的应激表型必须通过应激支持途径被癌细胞耐受。此外，对压力的适应是癌细胞生存所必需的，因此它们可能依赖于应激反应途径，而这些途径在正常细胞中通常不发挥如此重要的功能。因此，针对这些与压力适应相关的脆弱性显然是至关重要的，并为可能导致癌细胞选择性死亡的合成致命相互作用提供了巨大的机会。尽管癌细胞的应激表型非常重要，但我们对转化细胞中如何维持应激耐受性的遗传基础的理解存在很大差距，从而限制了我们的研究