AKT Signaling and Oxidative Stress Regulation of Erythropoiesis

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A tight coordination of erythroid cell division and maturation is required for daily production of erythroid cells and for immediate response to clinical conditions in which stress erythropoiesis is in demand. Mature erythroid progenitors and early erythroblasts (erythroid precursors) are highly proliferative, while proliferation decreases sharply in later stages. Elucidating molecular pathways that regulate erythroid cell differentiation and maturation is critical for devising targeted treatments for a number of erythroid disorders including erythroleukemias, thalassemias, and polycythemia vera. Signals generated from Erythropoietin (Epo) binding to its receptor erythropoietin receptor (EpoR) are mediated by JAK2 tyrosine kinase and are essential for normal erythroid cell development. Although the function of EpoR signaling in the regulation of erythroid survival and cell division has been characterized extensively, the impact of EpoR signaling on the transcriptional program of erythroid cell differentiation and maturation is less well understood. Particularly, not much is known about molecular mechanisms that coordinate erythroid precursor cell division, cell cycle exit, and differentiation and maturation. Evidence from our laboratory suggests that AKT serine threonine protein kinase mediates significant functions in the regulation of erythroid cell division and maturation downstream of EpoR signaling. We have identified AKT regulation of GATA-1 and FoxO3 transcription factors and mTOR kinase as critical for coordination of erythroid cell division and maturation. In addition our studies support the notion that regulation of physiological reactive oxygen species (ROS) by AKT target FoxO3 plays a significant role in erythroid cell maturation. ROS is thought to play a critical role in many erythroid disorders including in ¿-thalassemic erythropoiesis. Thus we propose a model in which signals downstream of AKT, specifically FoxO3, mTOR and GATA-1 coordinate erythroid precursor cell division and maturation and that this coordination is mediated at least in part by ROS. To investigate the validity of this model we propose the following aims: Aim 1: To investigate the role of FoxO3 in response to stress erythropoiesis; Aim 2: To elucidate the molecular mechanisms of erythroid cell proliferation in wild type and FoxO3 null mice; To investigate the mechanisms of AKT regulation of GATA-1. In these experiments we will evaluate the contribution of ROS and the role of mTOR. Finally we will examine the potential function of FoxO3 in ¿- thalassemia. Results from these studies will provide critical information on mechanisms of regulation of erythroid cell division and maturation, and should shed light on fundamental aspects of erythropoiesis.