Regulation of Hematopoiesis by Ribosomal Protein Paralogs

核糖体蛋白旁系同源物对造血的调节

• 批准号: 8816656
• 负责人: DAVID L. WIEST
• 金额: $ 21.97万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816656
• 关键词: Ablation; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Address; Affect; Amino Acid Sequence; Anemia; Animal Model; Automobile Driving; BMP4; Binding; Biogenesis; CD34 gene; Chimera organism; Collection; Data; Defect; Dependence; Development; Disease; Distal; Ectopic Expression; Equilibrium; Gene Silencing; Genes; Growth; Hematopoiesis; Hematopoietic stem cells; Human; Link; Messenger RNA; Molecular; Mus; Pathology; Pathway interactions; Physiological; Play; Positioning Attribute; Process; Production; Protein Binding; Proteins; RNA; RNA Binding; RNA Recognition Motif; Regulation; Ribosomal Proteins; Ribosomes; Role; Sequence Homology; Signal Transduction; Specificity; Staging; Stress; Structural Protein; Structure; Syndrome; T-Cell Development; T-Lymphocyte; Trans-Activators; Translational Repression; Translations; Yeasts; Zebrafish; base; biological adaptation to stress; clinically relevant; disease-causing mutation; fetal; human disease; insight; loss of function; mouse model; novel; paralogous gene; progenitor; public health relevance; skeletal; thymocyte

DESCRIPTION (provided by applicant): Ribosomopathies are a collection of diseases caused by mutations in the structural proteins of the ribosome or in proteins that facilitate ribosome biogenesis. It is widely held that the developmental abnormalities that characterize ribosomopathies result from a generalized defect in ribosome biogenesis or function. In contrast to this view, we postulate that ribosomal proteins (RP) have the capacity to bind cellular RNAs outside the context of the ribosome, and that some human diseases are in fact caused by disruption of such distinct, "extra-ribosomal" functions. In support of this hypothesis, we have identified a paralogous pair of RNA-binding RP, Rpl22 and its paralog Rpl22-Like1 (Like1), that are dispensable for both the biogenesis and function of ribosomes, yet perform critical regulatory roles in hematopoiesis. Furthermore, despite their high degree of homology (>70% identical in amino acid sequence), we demonstrate that Rpl22 and Like1 perform distinct functions, i.e., a p53-dependent role in development of �T lymphocytes and a Smad1-dependent role in driving hematopoietic stem cell (HSC) emergence, respectively. Importantly, not only do Rpl22 and Like1 perform distinct functions, but those functions are also mutually antagonistic. Indeed, the block in HSC emergence caused by knockdown of Like1 is rescued by eliminating Rpl22. The fact that the RNA binding helices of Rpl22 and Like1 are identical suggests that these proteins bind largely overlapping sets of RNA targets but have different effects on the activities of those targets. Thus, we now seek to understand how these highly homologous RP perform antagonistic functions that are critical at distinct stages of hematopoiesis. We will do so according to three aims: 1) To determine how systemic loss of Rpl22 causes a selective arrest of developing T cells. 2) To elucidate the basis for the antagonistic functions of Rpl22 and Like1. 3) To understand how the antagonistic balance of Rpl22 and Like1 controls HSC emergence by regulating Smad1.

描述（由申请人提供）：核糖体病是由核糖体结构蛋白或促进核糖体生物合成的蛋白突变引起的疾病的集合。人们普遍认为，核糖体病的发育异常是由于核糖体生物发生或功能的普遍缺陷造成的。与此观点相反，我们假设核糖体蛋白（RP）具有结合核糖体外的细胞RNA的能力，并且一些人类疾病实际上是由这种独特的“核糖体外”功能的破坏引起的。为了支持这一假设，我们已经鉴定了一对旁系同源的RNA结合RP，Rp 122及其旁系同源物Rp 122-Like 1（Like 1），它们对于核糖体的生物发生和功能都是同源的，但在造血中发挥关键的调节作用。此外，尽管它们具有高度同源性（氨基酸序列中>70%相同），我们证明Rp 122和Like 1执行不同的功能，即，分别是p53依赖的T淋巴细胞发育作用和Smad 1依赖的造血干细胞（HSC）出现作用。重要的是，Rp 122和Like 1不仅执行不同的功能，而且这些功能也是相互拮抗的。事实上，通过消除Rpl 22来挽救由Like 1的敲低引起的HSC出现的阻断。Rp 122和Like 1的RNA结合螺旋是相同的这一事实表明，这些蛋白质结合很大程度上重叠的RNA靶点组，但对这些靶点的活性具有不同的影响。因此，我们现在试图了解这些高度同源的RP如何执行拮抗功能，在造血的不同阶段是至关重要的。我们将根据三个目的这样做：1）确定Rp 122的全身性损失如何引起发育中的T细胞的选择性停滞。2)阐明Rp 122和Like 1拮抗功能的基础。3)为了了解Rp 122和Like 1的拮抗平衡如何通过调节Smad 1来控制HSC的出现。