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EpoR & Stat5 regulation of ribosome biogenesis and protein synthesis in erythropoiesis

EPR

基本信息

批准号：
10682214
负责人：
Merav Socolovsky
金额：
$ 51.52万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682214
关键词：
Address Back Biogenesis Biomass Bone Marrow CFU-E Cell Cycle Cell Enlargement Cell Lineage Cell Size Cell division Cells Compensation Complex Cues Cytokine Receptors Data Development Diamond-Blackfan anemia Disease Embryo Erythroblasts Erythrocytes Erythroid Erythropoiesis Erythropoietin FRAP1 gene Fetal Liver Genes Genetic Genetic Transcription Growth Growth Factor Hematopoiesis Hemoglobin Hormones Housekeeping Human Insulin Receptor Knowledge Life Link Malignant Neoplasms Mammalian Cell Measures Mediating Mediator Modeling Mus Mutation Nutritional PIK3CG gene Pathway interactions Phosphotransferases Process Protein Biosynthesis Protein Synthesis Induction Proteins Proteome Proto-Oncogene Proteins c-myc Publishing Receptor Protein-Tyrosine Kinases Regulation Ribosomal Proteins Ribosomal RNA Ribosomes S phase Signal Pathway Signal Transduction Speed Testing Time Transcript Translating Translations Work attenuation erythroid differentiation interest member novel overexpression pharmacologic pressure progenitor ribosomopathy self-renewal single-cell RNA sequencing transcriptomics

项目摘要

Project Summary Protein synthesis and ribosome biogenesis are the two most energy -intensive processes in a cell, resulting in their regulation through tight controls. EpoR, a member of the cytokine receptor superfamily, and its downstream mediator Stat5, are essential for erythropoiesis. The current proposal addresses novel regulation of ribosome biogenesis and protein synthesis by EpoR and Stat5 signaling during a key erythroid developmental decision. In recently published work we found that EpoR/ Stat5 stimulate shorter and more numerous cycles in early erythroblasts, while also promoting formation of larger erythroblasts that mature into larger red cells, in both mice and humans. This surprising finding suggests that EpoR/ Stat5 signaling alters the relationship between cell cycle duration and cell size, simultaneously inducing shorter cycles and exceptionally fast growth in biomass. In preliminary data supporting this hypothesis, single-cell RNA sequencing of Epor-/- and Stat5-/- fetal livers show dysregulated expression of ribosome biogenesis and translation genes. Further, we identified an EpoR/ Stat5-dependent sharp spike in the rate of rRNA transcription (~2.5 fold), protein synthesis rate (~4 to 6 fold) and rate of growth in cell size (~3 fold), that coincides with a key cell fate decision. It takes place as early erythroid progenitors known as CFU-e transition from self-renewal to erythroid terminal differentiation (ETD), becoming erythroblasts. The spike in protein synthesis at this time also coincides with an unusually short cell cycle. Immediately following the CFU-e/ETD transition, the rates of ribosome biogenesis and protein synthesis begin to decline back to baseline together with the decline in cell cycle speed, even though erythroblasts continue to divide and synthesize hemoglobin for an additional 3 to 5 cell divisions. The coincidence in the spikes of protein synthesis and ribosome biogenesis with cell cycle shortening at the CFU-e/ETD switch suggests that these processes are linked and may be functionally relevant to the switch. We will investigate the EpoR/Stat5- induced spike in protein synthesis with the following aims: Aim 1: Investigate the EpoR /Stat5 -induced spike in ribosome biogenesis & protein synthesis, determining the intracellular signaling pathways that are mediating this spike and identifying a potential subset of transcripts whose translation rate spikes. Aim 2: Determine causal relationships between the cell cycle, ribosome biogenesis, protein synthesis and cell size. The regulatory interactions between cell cycle duration, protein synthesis rate and cell size in mammalian cells are not well understood and yet are critical in development and in cancer. Aim 3: Test the hypothesis that the EpoR /Stat5 -induced spike in protein synthesis is required for erythroid differentiation. We will determine whether the EpoR-induced spike in protein synthesis is an 'Achilles heel' in mice deficient in the ribosomal protein Rpl11, a model of Diamond Blackfan Anemia, potentially explaining the selective sensitivity of the erythroid lineage to ribosomopathies.

蛋白质合成和核糖体生物合成是两个最耗能的过程细胞中的一个过程，导致它们通过严格控制进行调节。EpoR，细胞因子受体的成员超家族及其下游调节因子Stat 5对红细胞生成是必需的。现时的建议研究了在细胞分裂过程中，EpoR和Stat 5信号对核糖体生物发生和蛋白质合成的新调控。关键红细胞发育决策。在最近发表的工作中，我们发现EpoR/Stat 5刺激更短的时间，以及早期成红细胞中更多的周期，同时也促进更大的成红细胞的形成，成熟为更大的红细胞，在小鼠和人类中。这一令人惊讶的发现表明，EpoR/Stat 5 信号转导改变了细胞周期持续时间和细胞大小之间的关系，同时诱导更短的细胞周期。周期和生物量的异常快速增长。在支持这一假设的初步数据中， Epor-/-和Stat 5-/-胎肝的测序显示核糖体生物发生的表达失调，翻译基因此外，我们发现了一个EpoR/Stat 5依赖性的急剧尖峰的速率rRNA 转录（~2.5倍）、蛋白质合成速率（~4至6倍）和细胞大小的生长速率（~3倍），与一个关键的细胞命运决定相吻合它发生在早期红系祖细胞，称为CFU-e转换从自我更新到红细胞终末分化（ETD），成为成红细胞。蛋白质的峰值此时的合成也与异常短的细胞周期相一致。CFU-e/ETD后即刻在过渡期，核糖体生物合成和蛋白质合成的速率开始一起下降回到基线随着细胞周期速度的下降，即使成红细胞继续分裂和合成血红蛋白，再进行3到5次细胞分裂蛋白质合成和核糖体峰值的巧合在CFU-e/ETD开关处细胞周期缩短的生物发生表明这些过程是相互联系的，可以在功能上与开关相关。我们将研究EpoR/Stat 5诱导的蛋白质水平的尖峰，目的1：研究核糖体生物发生中EpoR /Stat 5诱导的尖峰信号，蛋白质合成，确定介导这种尖峰的细胞内信号传导途径，一个翻译率飙升的潜在转录子集。目标2：确定之间的因果关系细胞周期、核糖体生物发生、蛋白质合成和细胞大小。细胞之间的调节相互作用哺乳动物细胞中的周期持续时间、蛋白质合成速率和细胞大小还没有被很好地理解，在发育和癌症中至关重要。目的3：检验EpoR /Stat 5诱导的蛋白质峰值的假设合成是红细胞分化所必需的。我们将确定EpoR诱导的蛋白质峰值合成是核糖体蛋白Rpl 11缺陷小鼠的“阿喀琉斯之踵”，这是Diamond Blackfan的模型贫血，可能解释红细胞系对核糖体病的选择性敏感性。