Posttranscriptional Regulation of Genes Controling Cell Growth and Proliferation

控制细胞生长和增殖的基因的转录后调控

• 批准号: 6431425
• 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/6431425
• 关键词: RNA binding protein; apoptosis; biological signal transduction; cell cycle; cell growth regulation; cyclins; gene expression; human tissue; messenger RNA; oncoprotein p21; regulatory gene; stress; tissue /cell culture; tumor suppressor genes

In response to signals of either endogenous and exogenous origin, mammalian cells activate a series of events leading to changes in gene expression and to 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 regulatory mechanisms, which are less well understood, are also critically involved. These posttranscriptional events 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 molecules. Expression of p21, an inhibitor of cyclin-dependent kinases, is induced by various stresses (such as ultraviolet light) through stabilization of its mRNA by the RNA-binding protein HuR. Likewise, the expression of cyclins A and B1 throughout the cell division cycle is regulated through the cyclic association of their respective mRNAs with HuR, which results in transcript stabilization. Conversely, the decreased expression of cyclin D1 following treatment with the stress agent prostaglandin A2 is accomplished through cyclin D1 mRNA destabilization and is likely to involve the RNA-binding protein AUF1. Our efforts are 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. However, the mechanisms whereby pVHL exerts its tumor suppressive function remain to be determined. We are currently investigating pVHL's influence on gene expression by using SAGE analysis, and are seeking to identify proteins that interact with pVHL. We anticipate that these studies will help elucidate pVHL's function and its tumor suppressor properties.

为了响应内源性和外源性起源的信号，哺乳动物细胞激活一系列事件，导致基因表达变化以及全球细胞反应的实施。虽然对调节基因表达变化的转录事件已经进行了彻底的研究，但越来越清楚的是，文字后调节机制的理解较低，也被严格涉及。 这些转录后事件包括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分子表达的机制。 p21的表达是细胞周期蛋白依赖性激酶的抑制剂，通过通过RNA结合蛋白HUR稳定其mRNA的各种应力（例如紫外线）诱导。 同样，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的环节相关性受到调节，从而导致转录本稳定。 相反，用胁迫剂前列腺素A2处理后，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，并且很可能涉及RNA结合蛋白AUF1。 我们的努力集中在寻找RNA结合蛋白，靶标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。肿瘤抑制基因von Hippel-lindau（PVHL）的产物可将基因表达在转录水平上调节基因表达和MRNA STERTADE，MRNA StET，MRNA STERTINE，MRNA STERTION。 但是，PVHL发挥其肿瘤抑制功能的机制仍有待确定。 我们目前正在通过使用SAGE分析研究PVHL对基因表达的影响，并试图鉴定与PVHL相互作用的蛋白质。 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。