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Principal Investigator: Merav Socolovsky
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2024
Award: $494,603
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <1-Phosphatidylinositol 3-Kinase><Address><Back><Biogenesis><Biomass><Blood erythrocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><CFU-E><Cancers><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Enlargement><Cell Growth in Size><Cell Lineage><Cell Signaling><Cell Size><Cell division><Cells><Compensation><Complex><Cues><Cytokine Receptors><Data><Development><Diamond-Blackfan anemia><Disease><Disorder><Dorsum><ECSF><Embryo><Embryonic><Endocrine Gland Secretion><Epoetin><Erythroblasts><Erythrocytes><Erythrocytic><Erythroid><Erythroid Colony-Forming Units><Erythropoiesis><Erythropoietin><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fetal Liver><Gene Transcription><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Growth><Growth Agents><Growth Factor><Growth Substances><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Hemoglobin><Hormones><Housekeeping><Housework><Human><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin-Dependent Tyrosine Protein Kinase><Intracellular Communication and Signaling><Kinases><Knowledge><Life><Link><MYC Transcription Factor><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Marrow erythrocyte><Measures><Mechanistic Target of Rapamycin><Mediating><Mediator><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutation><Normoblasts><Nucleated Erythrocytes><Nucleated red blood cell><Nucleated red cell><Nutritional><Origin of Life><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PTK Receptors><Pathway interactions><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphotransferase Gene><Phosphotransferases><Process><Protein Biosynthesis><Protein Synthesis Induction><Proteins><Proteins Growth Factors><Proteome><Proto-Oncogene Products c-myc><Proto-Oncogene Proteins c-myc><PtdIns 3-Kinase><Publishing><RAFT1><RNA Expression><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Red Blood Cells><Red Cell><Regulation><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal Proteins><Ribosomal RNA><Ribosomes><S Period><S phase><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Synthesis Period><Synthesis Phase><Testing><Therapeutic Hormone><Time><Tissue Growth><Transcript><Transcription><Translating><Translations><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Work><attenuation><biological signal transduction><blood cell formation><blood corpuscles><c-myc Proteins><developmental><erythrocyte colony stimulating factor><erythroid development><erythroid differentiation><genome mutation><hematopoietin><interest><mTOR><malignancy><mammalian target of rapamycin><member><myc Proto-Oncogene Product p62><myc Proto-Oncogene Proteins><neoplasm/cancer><novel><nucleated RBCs><nutritious><ontogeny><overexpress><overexpression><pathway><pharmacologic><pressure><progenitor><protein synthesis><rRNA><ribosomopathy><scRNA-seq><self-renew><self-renewal><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><transcriptomics><translation>