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: 7592008
• 负责人: MYRIAM none GOROSPE
• 金额: $ 121.4万
• 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/7592008
• 关键词: AMP-activated protein kinase kinase; Aging; BRF1 gene; Binding; Blood Vessels; Cell Cycle; Cells; Dissociation; Event; Fibroblasts; Gene Expression; Gene Expression Regulation; Genes; Goals; Half-Life; Heterogeneous Nuclear RNA; Mammalian Cell; Messenger RNA; MicroRNAs; Modification; Nuclear; Numbers; Pattern; Peptide Signal Sequences; Phosphotransferases; Process; Proteins; RNA-Binding Proteins; Rate; Regulator Genes; Reporting; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stress; System; Translations; Work; alpha Karyopherins; angiogenesis; biological adaptation to stress; cancer cell; cell growth; interest; mRNA Decay; mRNA Precursor; mRNA Stability; malignant phenotype; nucleocytoplasmic transport; programs; response; senescence; thymidine 5' -triphosphate; AMP-activated protein kinase kinase; Aging; BRF1 gene; Binding; Blood Vessels; Cell Cycle; Cells; Dissociation; Event; Fibroblasts; Gene Expression; Gene Expression Regulation; Genes; Goals; Half-Life; Heterogeneous Nuclear RNA; Mammalian Cell; Messenger RNA; MicroRNAs; Modification; Nuclear; Numbers; Pattern; Peptide Signal Sequences; Phosphotransferases; Process; Proteins; RNA-Binding Proteins; Rate; Regulator Genes; Reporting; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stress; System; Translations; Work; alpha Karyopherins; angiogenesis; biological adaptation to stress; cancer cell; cell growth; interest; mRNA Decay; mRNA Precursor; mRNA Stability; malignant phenotype; nucleocytoplasmic transport; programs; response; senescence; thymidine 5' -triphosphate

In response to signals of either endogenous or exogenous origins, mammalian cells implement changes in gene expression patterns that profoundly influence the global response of the cell. While the transcriptional events regulating changes in gene expression have been thoroughly studied, post-transcriptional processes, which are less well understood, are emerging as major gene regulatory mechanisms. Post-transcriptional gene regulation includes pre-mRNA processing and maturation, mRNA transport, stability and translation, as well as protein processing, modification and degradation. We are keenly interested in investigating the mechanisms that regulate the expression of proliferation-associated, cell cycle-regulatory, and stress-response gene products. To this end, we have focused specifically on sequence-specific RNA-binding proteins that regulate mRNA stability and translation. Our work on the RNA-binding protein HuR illustrates the approaches and scope of our studies. We previously characterized the roles of HuR as a protein that can stabilize target mRNAs and sometimes promote their translation. We have identified a large number of its target mRNAs, have elucidated a signature motif present in them, and have studied its nucleocytoplasmic shuttle, including an import factor (importin-alpha 1) and kinase (AMPK) responsible for its nuclear localization. More recently, we have identified CHK2 (checkpoint 2) as a kinase that influences HuR binding to target mRNAs, including the sirtuin-1 (Sirt1) mRNA. Our studies have demonstrated a clear role for HuR in regulating the expression of stress-response and proliferation genes in both primary, untransformed cells (fibroblasts, vascular smooth muscle cells, etc) and in cancer cells of various types. In the latter cell systems, HuR appears to increase the malignant phenotype by promoting proliferation, increasing angiogenesis, diminishing the cells ability to undergo senescence, and inhibiting apotosis. We have also extended our efforts to other RNA-binding proteins that either promote mRNA decay (AUF1, TTP, BRF1, KSRP) or suppress translation (TIAR, TIA-1). Over the past year, we have elucidated a signature motif for TIAR which was unexpectedly C-rich and triggered the dissociation of target mRNAs from TIAR in response to stress. We have also reported that many of these regulatory RBPs can influence the expression of other RBPs through binding to cognate mRNAs.

为了响应内源性或外源性起源的信号，哺乳动物细胞在基因表达模式中实现了严重影响细胞全球反应的基因表达模式的变化。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，但在不了解的转录过程中却被视为主要基因调节机制。转录后基因调节包括MRNA前的加工和成熟，mRNA转运，稳定性和翻译以及蛋白质加工，修饰和降解。 我们对研究调节增殖相关，细胞周期调节和应激反应基因产物的表达的机制非常感兴趣。为此，我们专门针对调节mRNA稳定性和翻译的序列特异性RNA结合蛋白。我们在RNA结合蛋白HUR上的工作说明了我们研究的方法和范围。我们以前将HUR的作用描述为可以稳定目标mRNA并有时促进其翻译的蛋白质。我们已经确定了大量其靶标mRNA，阐明了其中存在的签名基序，并研究了其核细胞质的班车，包括导入因子（Importin-Alpha 1）和激酶（AMPK）（AMPK）负责其核定位。 最近，我们将CHK2（检查点2）确定为一种激酶，它影响了与靶标mRNA结合的激酶，包括Sirtuin-1（SIRT1）mRNA。 我们的研究表明，HUR在调节原发性，未转化细胞（成纤维细胞，血管平滑肌细胞等）和各种类型的癌细胞中的应激反应和增殖基因表达方面起着明显的作用。在后一种细胞系统中，HUR似乎通过促进增殖，增加血管生成，降低细胞经历衰老的能力并抑制凋亡的能力来增加恶性表型。 我们还将精力扩展到其他RNA结合蛋白，这些RNA结合蛋白要么促进mRNA衰变（AUF1，TTP，BRF1，KSRP）或抑制翻译（TIAR，TIA-1）。在过去的一年中，我们阐明了TIAR的签名图案，该基序意外地富含C，并触发了目标mRNA与TIAR的解离，以响应压力。 我们还报告说，其中许多调节RBP可以通过与同源mRNA结合来影响其他RBP的表达。