Date of Award

5-2008

Document Type

On-Campus Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Interdisciplinary Program

Research Advisor

Paul A. Ney, M.D.

Committee

Linda C. Harris, Ph.D. Linda M. Hendershot, Ph.D. David R. Nelson, Ph.D. Richard J. Smeyne, Ph.D.

Keywords

terminal erythroid differentiation, EPOR, STAT5, survival, Friend disease, c-MYB, GATA1, mitochondrial clearance, BCL2 family proteins, NIX

Abstract

Terminal erythroid differentiation is a precisely regulated process, in which mature red blood cells are generated from late erythroid progenitor cells. Regulation of cellular proliferation, survival and differentiation determines the fate of those cells. Extracellular signaling molecule, particularly erythropoietin (EPO), plays a critical role in this process by activating its receptor (EPOR) which is highly expressed in late erythroid progenitor cells. Although the molecular mechanisms of how EPOR signaling functions have not been entirely elucidated, evidence from genetic studies demonstrated its indispensable role for erythroid survival. In this study, we used Friend disease as a model system to understand the role of EPOR signaling in both Friend disease and normal erythropoiesis. Here we showed that EPOR signaling is not essential for Friend virus-mediated erythroblastosis. However, both EPOR and signal transducer and activation of transcription 5 (STAT5), one of its downstream components, are required for Friend virus-induced polycythemia. Those evidence suggested a STAT5-dependent mechanism to regulate erythroid differentiation. Further studies showed that EPOR signaling has a novel role to induce terminal differentiation in Friend virus anemia strain infected erythroblast (FVA) cells, characterized by exiting cell cycle and expressing erythroid marker genes, which is independent of its established role in survival. More importantly, FVA cells lacking the STAT5 activation fail to undergo terminal differentiation in response to EPO. Taken together, our data support a novel instructive function of EPOR signaling and this function requires STAT5.

DOI

10.21007/etd.cghs.2008.0375

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