Translational Control of Cancer

描述（由申请人提供）：癌症目前是美国第二大死亡原因，每年死亡率的大约四分之一是由它造成的。我们怀疑可能存在致癌信号汇聚的细胞机制的共同组成部分，并且这些关键的调节节点可能代表新疗法的分子靶点。我的方法来自于最近对人类乳腺癌和小鼠淋巴恶性肿瘤的研究，该研究确定了帽依赖性蛋白质合成机制，特别是真核起始因子4E（elF4E），作为致癌信号会聚和扩增的关键点。我打算定义细胞周期动力学诱导后的elF4E表达在静止的成纤维细胞窝藏米非司酮诱导elF4E构建，并确定哪些转录编码细胞周期调节剂被招募到多核糖体时，异位elF4E触发细胞周期进入。最后，我计划使用新的核苷为基础的elF4E拮抗剂，以确定elF4E活性，帽依赖性蛋白质的合成，招聘的转录编码特定的细胞周期调节剂和细胞周期的动力学进入之间的关系。靶向参与帽依赖性翻译的机制的长期目标是提供一种新的药物开发途径，其逆转癌症，从而改善人类健康。

DESCRIPTION (provided by applicant): Cancer is currently the 2nd leading cause of death in the U.S., responsible for approximately one quarter of the annual death rate. We suspect there may be common components of the cellular machinery where oncogenic signals converge, and that these critical regulatory nodes may represent molecular targets for new therapies. My approach derives from recent work on human breast carcinoma and murine lymphoid malignancies, which identifies the cap-dependent protein synthesis machinery, specifically eukaryotic initiation factor 4E (elF4E), as a critical point of convergence and amplification of oncogenic signals. I intend to define cell cycle kinetics after induction of elF4E expression in quiescent fibroblasts harboring a mifipristone inducible elF4E construct, and determine which transcripts encoding cell cycle regulators are recruited to polyribosomes when ectopic elF4E triggers cell cycle entry. Finally I plan on using novel nucleoside-based elF4E antagonists to define the relationships among elF4E activity, cap-dependent protein synthesis, recruitment of transcripts encoding specific cell cycle regulators and the kinetics of cell cycle entry. The long term goal of targeting the machinery involved in cap-dependent translation is to provide a novel avenue of drug development which reverses cancer and thereby improves human health.