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  • Erythropoiesis involves the proliferation and


    Erythropoiesis involves the proliferation and differentiation of hematopoietic stem CPI-455 to mature RBCs. This process is a tightly-regulated to adjust rates of RBC production based on physiologic need. Fas-mediated apoptosis is one mechanism that controls erythropoiesis. The role of Fas-signaling has been studied in normal erythropoiesis where a negative feedback loop exists between FasL+ mature erythroblasts and Fas+ immature blasts to regulate the production of new erythrocytes. However, increasing levels of erythropoietin blocks this pathway to allow for enhanced RBC production during times of physiological need [60]. Our findings demonstrate that Saf levels increase during human erythroid maturation, and expression of Saf lncRNA reduces surface expression of Fas and protects cells from Fas-mediated cell death signals. Saf is known to regulate the production of Fas transcripts that lack the transmembrane domain, thereby producing soluble Fas (sFas) protein [25], [26]. sFas acts as an anti-apoptotic protein by binding to Fas ligand expressed on adjacent cells and preventing activation of Fas receptors on target cells [61], [62]. Our data indicate that lncRNA Saf has a role in the maintenance of RBC production. In future studies, a more complete understanding of the role for Saf at distinct stages of terminal erythroid differentiation could be accomplished by FACS-based methods to enrich populations using surface markers described here, glycophorin A (CD235) and transferrin receptor (CD71), in combination with band 3 and α4-integrin [63], [64]. In summary, we suggest that Saf is regulated by GATA-1, KLF1, and NF-κB and according with the Saf expression pattern in our CD34+ culture model we propose that expression of Saf is fundamentally important for terminal erythroid differentiation.
    Author contributions
    Conflict of interest
    Acknowledgments We thank the flow cytometry laboratory of Melissa Roberts for expertise in flow cytometry and cell sorting. This work was supported by a Medical Innovators Grant from the Doris Duke Charitable Foundation (Award Number 2010037) (D.A.P. and A.W.). The Southern Illinois University School of Medicine flow cytometry equipment was supported by Award Number S10RR025674 from the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
    List of abbreviations
    Introduction Protein kinase is one of the largest gene family consists of 518 genes (Rubin et al., 2000, Manning et al., 2002) and categorized into (i) serine/threonine kinases, (ii) tyrosine kinases and (iii) tyrosine kinase like proteins. Kinase members are the major class of potential drug targets of varieties of diseases including cancer, type II diabetes and neurodegenerative diseases (Naz et al., 2013, Naz et al., 2015a, Naz et al., 2015b, Naz et al., 2016a, Naz et al., 2016b, Jameel et al., 2017, Naz et al., 2017). Fas-activated serine/threonine kinase (FASTK) contributes to several biological functions by phosphorylating different substrates. This protein is a member of the serine/threonine protein kinase family encoded by FASTK gene. Human FASTK (EC is a 51-kDa mitochondria associated protein, which helps to protect the cells under various adverse environmental conditions (Li et al., 2004a, Li et al., 2004b). FASTK becomes activate during the Fas-mediated apoptosis via phosphorylation of translational repressor T cell intracellular Ag-1 (TIA1), which precede the onset of DNA fragmentation. Using yeast two-hybrid screen, FASTK has reported previously as a TIA1-interacting protein (Tian et al., 1995). TIA1 is an RNA-binding protein, involved in translational control pathway. Under stress conditions, FASTK may release from mitochondria and interacts with TIA1. It inhibits the activity of TIA1 to promote the inhibition of apoptosis. These results are suggesting that FASTK may act as a survival protein and promotes the inhibition of Fas-and UV-induced apoptosis (Li et al., 2004a, Li et al., 2004b). Subcellular fractionation analysis suggests that FASTK is a mitochondrial component tethered by a lysine/arginine-rich domain at C-terminus (Li et al., 2004b).