Posttranscriptional Regulation Of Genes Cell Growth

基因细胞生长的转录后调控

• 批准号: 6501322
• 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/6501322
• 关键词: RNA binding protein; biological signal transduction; cell growth regulation; cell proliferation; cyclins; developmental genetics; gene induction /repression; human tissue; messenger RNA; oncoprotein p21; posttranscriptional RNA processing; serial analysis of gene expression; tissue /cell culture; tumor suppressor proteins

In response to signals of either endogenous or exogenous origin, mammalian cells activate a series of events leading to changes in gene expression. These alterations in gene expression, in turn, directly participate in the implementation of a global cellular response. While the transcriptional events regulating such changes in gene expression have been thoroughly studied, it is becoming increasingly clear that posttranscriptional events, which are less well understood, are also major regulatory mechanisms that profoundly modify gene expression. Posttranscriptional events of gene regulation include mRNA processing, transport, stability and translation, as well as protein processing, phosphorylation and degradation. With respect to mRNA stability, we are investigating the mechanisms regulating the expression of various cell cycle regulatory and growth regulatory genes. We have shown that induction of the cyclin-dependent kinase inhibitor p21 by ultraviolet light and other stresses occurs through stabilization of its mRNA by the RNA-binding protein HuR. Likewise, the expression of cyclins A and B1 throughout the cell division cycle was shown to be regulated through the cyclic association of their respective mRNAs with HuR, which results in transcript stabilization during the S phase. We have recently reported that high levels of HuR expression in young human fibroblasts contributes to the heightened presence of cyclins A and B1, as HuR stabilizes their mRNAs. Conversely, in senescent human fibroblasts, lower HuR levels directly results in reduced stability, and hence expression, of cyclin A and cyclin B1 mRNAs. Other studies have shown that decreased expression of cyclin D1 following treatment with the stress agent prostaglandin A2 was accomplished through cyclin D1 mRNA destabilization and likely involved the RNA-binding protein AUF1. Our long-term efforts are thus focused on searching for RNA-binding proteins, target mRNA regions, and signaling pathways involved in regulating the stability of mRNAs encoding growth control and cell cycle regulatory genes. The product of the tumor suppressor gene von Hippel- Lindau (pVHL) is believed to modulate gene expression at the levels of transcription elongation, mRNA stability and protein degradation. We are currently investigating pVHL's global influence on gene expression using SAGE analysis, as well as its influence on TNF-alpha mRNA expression specifically. We anticipate that these studies will help elucidate pVHL's function and its tumor suppressor properties.

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。基因表达的这些改变反过来直接参与了全局细胞反应的实施。虽然对调节基因表达中这种变化的转录事件进行了彻底的研究，但越来越清楚的是，文字后事件的理解较低，也是深刻地改变基因表达的主要调节机制。基因调节的转录后事件包括mRNA处理，运输，稳定性和翻译，以及蛋白质加工，磷酸化和降解。 关于mRNA稳定性，我们正在研究调节各种细胞周期调节和生长调节基因表达的机制。我们已经表明，紫外线诱导细胞周期蛋白依赖性激酶抑制剂p21和其他应力是通过通过RNA结合蛋白HUR稳定其mRNA而发生的。同样，在整个细胞分裂周期中，细胞周期蛋白A和B1的表达通过其各自的mRNA与HUR的循环结合来调节，从而导致在S相期间转录本稳定。我们最近报告说，由于HUR稳定其mRNA，因此年轻人类成纤维细胞中的HUR表达较高，有助于细胞周期蛋白A和B1的存在。相反，在衰老的人成纤维细胞中，较低的HUR水平直接导致细胞周期蛋白A和细胞周期蛋白B1 mRNA的稳定性降低，因此表达。其他研究表明，用胁迫剂前列腺素A2治疗后细胞周期蛋白D1的表达降低是通过细胞周期蛋白D1 mRNA不稳定完成的，并且可能涉及RNA结合蛋白AUF1。因此，我们的长期努力集中在寻找RNA结合蛋白，靶mRNA区域以及涉及调节编码生长控制和细胞周期调节基因的mRNA稳定性的信号通路。 据信肿瘤抑制基因von Hippellindau（PVHL）的乘积在转录伸长，mRNA稳定性和蛋白质降解水平下调节基因表达。我们目前正在使用SAGE分析研究PVHL对基因表达的全球影响，并特别针对TNF-Alpha mRNA表达的影响。我们预计这些研究将有助于阐明PVHL的功能及其肿瘤抑制特性。