Posttranscriptional Gene Regulation Of Cell Growth

细胞生长的转录后基因调控

• 批准号: 6815187
• 负责人: MYRIAM none GOROSPE
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6815187
• 关键词: RNA binding protein; biological signal transduction; cell growth regulation; cell proliferation; cyclins; gene induction /repression; human tissue; messenger RNA; posttranscriptional RNA processing; serial analysis of gene expression; tissue /cell culture

In response to signals of either endogenous or exogenous origin, mammalian cells activate a series of events leading to changes in gene expression. In turn, these alterations in gene expression directly influence the global response of the cell. While the transcriptional events regulating such changes in gene expression have been thoroughly studied, posttranscriptional events, which are less well understood, are emerging as major gene regulatory mechanisms. Posttranscriptional gene regulation includes mRNA processing, transport, stability and translation, as well as protein processing, modification and degradation. With respect to mRNA stability, we are investigating the mechanisms that regulate the expression of various cell cycle regulatory and proliferation-associated genes. We have shown that the function of the RNA-binding protein HuR, which stabilizes transcripts encoding proliferative genes, is strongly regulated by the AMP-activated kinase (AMPK). AMPK promotes the nuclear localization of HuR and thus prevents the stabilization of HuR targets. With respect to translation, we have recently demonstrated that HuR also participates in enhancing protein synthesis from target mRNAs, such as that encoding the tumor suppressor p53. Our long-term efforts are focused on investigating RNA-binding proteins, target mRNA regions, and signaling pathways effecting post-transcriptional gene regulation on growth control and cell cycle regulatory factors.

为了响应内源性或外源性起源的信号，哺乳动物细胞激活一系列事件，导致基因表达变化。反过来，基因表达的这些改变直接影响细胞的全局反应。尽管已经对调节基因表达变化的转录事件进行了彻底的研究，但未知的转录后事件正在成为主要的基因调节机制。转录后基因调节包括mRNA处理，运输，稳定性和翻译，以及蛋白质加工，修饰和降解。关于mRNA稳定性，我们正在研究调节各种细胞周期调节和增殖相关基因表达的机制。我们已经表明，稳定编码增生基因的转录本的RNA结合蛋白HUR的功能受AMP激活激酶（AMPK）的强烈调节。 AMPK促进了HUR的核定位，因此防止了HUR目标的稳定。在翻译方面，我们最近证明了HUR还参与了来自靶MRNA的蛋白质合成，例如编码肿瘤抑制p53的蛋白质合成。我们的长期努力集中在研究RNA结合蛋白，靶mRNA区域以及影响转录后基因调节的信号通路对生长控制和细胞周期调节因子的影响。