Transcriptional Repression by Maf1 in Yeast

酵母中 Maf1 的转录抑制

基本信息

批准号：
8265966
负责人：
IAN M WILLIS
金额：
$ 45.85万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265966
关键词：
Address Affect Bacteria Behavior Biochemical Biochemical Genetics Biological Biological Testing Cancer Biology Cell Cycle Cell Nucleus Cell Survival Cell division Cell physiology Cells Complex Cyclic AMP-Dependent Protein Kinases Cytoplasm DNA-Directed RNA Polymerase Databases Event Genetic Genetic Screening Genetic Transcription Goals Homologous Gene Human In Vitro Knowledge Link Mammalian Cell Mammals Maps Mediator of activation protein Metabolic Methods Modeling Modification Mutation Nuclear Nuclear RNA Nucleotides Nutritional Oncogenes Pathway interactions Phosphopeptides Phosphotransferases Polymerase Population Process Property Protein Kinase Proteins RNA Polymerase I RNA Polymerase III Recombinants Recycling Regulation Repression Research Ribosomal RNA Ribosomes Roentgen Rays Role Saccharomyces cerevisiae Signal Pathway Signal Repression Signal Transduction Signaling Molecule Site Solutions Specific qualifier value Stress Structure Structure-Activity Relationship System Testing Transcription Repressor/Corepressor Transfer RNA Tumor Suppressor Proteins Yeasts analytical ultracentrifugation c-myc Genes cost fitness gel electrophoresis gene repression genome-wide in vivo innovation insight loss of function mutation mutant novel protein folding protein structure public health relevance research study response three dimensional structure tumor

项目摘要

DESCRIPTION (provided by applicant): The synthesis of rRNAs and tRNAs is intimately linked with cell division through the function of tumor suppressors (e.g. p53 and Rb) and oncogenes (e.g. c-myc). The transforming forms of these proteins directly target and up-regulate transcription by RNA polymerases (pols) I and III along with the expression of important cell cycle regulators. The Maf1 protein is a unique regulator of transcription whose properties in human cells are similar to p53 and Rb. Human Maf1 is a candidate tumor suppressor that negatively regulates transcription by all three nuclear RNA polymerases. How Maf1 achieves its effects on transcription is not understood and is complicated by the fact that the protein does not contain any motifs of known function. In S. cerevisiae, Maf1 is essential for repressing transcription by RNA polymerase III and functions to integrate the responses from multiple nutritional and stress signaling pathways that coordinately regulate ribosome and tRNA synthesis. These pathways, like Maf1 itself, are not well defined. The universal requirement for Maf1 in pol III transcriptional repression in yeast provides an extraordinarily valuable model for understanding the pathways and mechanisms regulating ribosome and tRNA synthesis and the biochemical function of this novel signal integrator. Accordingly, the long-term goal of this research is to understand Maf1 structure/function relationships, its interactions with regulatory targets and its interactions with upstream signaling molecules that operate via posttranslational mechanisms to affect Maf1-dependent transcriptional repression. These aims will be achieved through biochemical studies in well-defined in vitro systems and through the application of an innovative method for phosphopeptide identification. In addition, powerful genome-wide and systematic genetic and biochemical approaches will be used to identify protein kinases and other molecules involved in signaling repression by Maf1. Finally, our understanding of the function and regulation of Maf1 will be advanced by the determination its three-dimensional structure. PUBLIC HEALTH RELEVANCE: Maf1 is a potential tumor suppressor that negatively regulates transcription by all three nuclear RNA polymerase in mammalian cells. In yeast, Maf1 is an essential mediator of transcriptional repression by RNA polymerase III and integrates the responses from multiple nutritional and stress signaling pathways that coordinately regulate ribosome and tRNA synthesis. Our genetic, biochemical and structural studies on on Maf1 will enhance understanding of fundamental cellular processes that are likely to impact cancer biology.

描述（由申请人提供）：rRNA 和 tRNA 的合成通过肿瘤抑制因子（例如 p53 和 Rb）和癌基因（例如 c-myc）的功能与细胞分裂密切相关。这些蛋白质的转化形式直接靶向并上调 RNA 聚合酶 (pols) I 和 III 的转录以及重要细胞周期调节因子的表达。 Maf1 蛋白是一种独特的转录调节因子，其在人类细胞中的特性与 p53 和 Rb 相似。人 Maf1 是一种候选肿瘤抑制因子，可负向调节所有三种核 RNA 聚合酶的转录。 Maf1 如何实现其对转录的影响尚不清楚，并且由于该蛋白质不包含任何已知功能的基序这一事实而变得复杂。在酿酒酵母中，Maf1 对于抑制 RNA 聚合酶 III 的转录至关重要，其功能是整合多种营养和应激信号通路的反应，协调调节核糖体和 tRNA 的合成。这些途径，就像 Maf1 本身一样，没有明确定义。酵母中 pol III 转录抑制对 Maf1 的普遍需求为理解调节核糖体和 tRNA 合成的途径和机制以及这种新型信号整合器的生化功能提供了一个非常有价值的模型。因此，这项研究的长期目标是了解 Maf1 结构/功能关系、其与调控靶点的相互作用以及其与上游信号分子的相互作用，这些信号分子通过翻译后机制影响 Maf1 依赖性转录抑制。这些目标将通过在明确的体外系统中进行生化研究以及应用磷酸肽鉴定的创新方法来实现。此外，强大的全基因组和系统的遗传和生化方法将用于识别蛋白激酶和其他参与 Maf1 信号抑制的分子。最后，通过确定Maf1的三维结构，将加深我们对Maf1功能和调控的理解。公共卫生相关性：Maf1 是一种潜在的肿瘤抑制因子，可负调节哺乳动物细胞中所有三种核 RNA 聚合酶的转录。在酵母中，Maf1 是 RNA 聚合酶 III 转录抑制的重要介质，并整合多种营养和应激信号通路的反应，协调调节核糖体和 tRNA 合成。我们对 Maf1 的遗传、生化和结构研究将增强对可能影响癌症生物学的基本细胞过程的理解。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The yeast magmas ortholog pam16 has an essential function in fermentative growth that involves sphingolipid metabolism.

酵母岩浆直系同源物 pam16 在涉及鞘脂代谢的发酵生长中具有重要功能。

DOI：
10.1371/journal.pone.0039428
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Short,MaryK;Hallett,JoshuaP;Tar,Krisztina;Dange,Thomas;Schmidt,Marion;Moir,Robyn;Willis,IanM;Jubinsky,PaulT
通讯作者：
Jubinsky,PaulT

Eukaryotic cells producing ribosomes deficient in Rpl1 are hypersensitive to defects in the ubiquitin-proteasome system.