NACA is a positive regulator of human erythroid-cell differentiation

Sophie Lopez,Patrice Dubreuil,Sophie Gomez,René St Arnaud,Serge Fichelson,Nicole Berda,Jean-RéMy Galindo,Laetitia Stuhl,Anne Dubart-Kupperschmitt,Anne Murati

doi:10.1242/jcs.02295

Abstract

We have previously identified the transcript encoding NACA (the alpha chain of the nascent-polypeptide-associated complex) as a cytokine-modulated specific transcript in the human TF-1 erythroleukemic cell line. This protein was already known to be a transcriptional co-activator that acts by potentiating AP-1 activity in osteoblasts, and is known to be involved in the targeting of nascent polypeptides. In this study, we investigate the role of NACA in human hematopoiesis. Protein distribution analyses indicate that NACA is expressed in undifferentiated TF-1 cells and in human-cord-blood-derived CD34(+) progenitor cells. Its expression is maintained during in vitro erythroid differentiation but, in marked contrast, its expression is suppressed during their megakaryocytic or granulocytic differentiation. Ectopic expression of NACA in CD34(+) cells under culture conditions that induce erythroid-lineage differentiation leads to a marked acceleration of erythroid-cell differentiation. Moreover, ectopic expression of NACA induces erythropoietin-independent differentiation of TF-1 cells, whereas downregulation of NACA by RNA interference abolishes the induction of hemoglobin production in these cells and diminishes glycophorin-A (GPA) expression by CD34(+) progenitors cultured under erythroid differentiation conditions. Altogether, these results characterize NACA as a new factor involved in the positive regulation of human erythroid-cell differentiation.

Highlights

The molecular mechanisms that control determination, selfrenewal and differentiation of hematopoietic cells are tightly regulated through both extrinsic and intrinsic signals
Ectopic expression of nascent-polypeptide-associated complex (NACA) induces erythropoietin-independent differentiation of TF-1 cells, whereas downregulation of NACA by RNA interference abolishes the induction of hemoglobin production in these cells and diminishes glycophorin-A (GPA) expression by CD34+ progenitors cultured under erythroid differentiation conditions
These results characterize NACA as a new factor involved in the positive regulation of human erythroid-cell differentiation

Summary

Introduction

The molecular mechanisms that control determination, selfrenewal and differentiation of hematopoietic cells are tightly regulated through both extrinsic and intrinsic signals. In the erythroid-cell lineage (a subclass of the myeloid lineages), in addition to the well-established role of both the erythropoietin/erythropoietinreceptor (Epo/Epo-R) pair and the GATA1 transcription factor, other extrinsic signaling molecules including Wnt/frizzled (Van Den Berg et al, 1998), TGFβ (Zermati et al, 2000), fibroblast growth factors (Huber et al, 1998), growth-factorindependence 1B (Osawa et al, 2002), insulin and insulin-like growth factor (Miyagawa et al, 2000), and intrinsically acting factors such as caspases (Zermati et al, 2001) have been reported to be important for erythropoiesis. Further identification of either novel molecules or complex sets of interactions between already-identified crucial transcription factors and co-factors might help to elucidate the molecular mechanisms that control the myeloid differentiation process

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