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Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia

Oncogene volume 19, pages 2296–2304 (2000)Cite this article

Abstract

We have recently isolated the erythroleukemic cell line, HB60-5, that proliferates in the presence of erythropoietin (Epo) and stem cell factor (SCF), but undergoes terminal differentiation in the presence of Epo alone. Ectopic expression of the ets related transcription factor Fli-1 in these cells resulted in the establishment of the Epo-dependent cell line HB60-ED that proliferates in the presence of Epo. In this study, we utilized these two cell lines to examine the signal transduction pathways that are activated in response to Epo and SCF stimulation. We demonstrate that Epo, but not SCF, phosphorylates STAT-5 in both HB60-5 and HB60-ED cells. Interestingly, SCF activates the Shc/ras pathway in HB60-5 cells while Epo does not. However, both Epo and SCF are capable of activating the Shc/ras pathway in HB60-ED cells. Furthermore, enforced expression of gp55 in HB60-5 cells by means of infection with the Spleen Focus Forming virus-P (SFFV-P), confers Epo independent growth, which is associated with the up-regulation of Fli-1. Activation of the Shc/ras pathway is readily detected in gp55 expressing cells in response to both Epo and SCF, and is associated with a block in STAT-5B tyrosine phosphorylation. These results suggest that STAT-5 activation, in the absence of Shc/ras activation, plays a role in erythroid differentiation. Moreover, Fli-1 is capable of switching Epo-induced differentiation to Epo-induced proliferation, suggesting that this ets factor regulated genes whose products modulate the Epo-Epo-R signal transduction pathway.

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Acknowledgements

We thank Dr Jane McGlade for the generous gift of Shc antibody. We also thank Drs Kirill Rosen for his comment on the manuscript and Lynda Woodcock for help in preparation of the manuscript. This work was supported by grants from the National Cancer Institute of Canada to Y Ben-David and SA Berger and Medical Research Council of Canada to D Dumont. RR Higgins was supported by a fellowship from the Leukemia Research Fund of Canada.

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Author notes

  1. Jeff Howard

    Present address: HULC Cell & Molecular Biology Laboratory, Lawson Research Institute, St. Joseph's Health Centre, 268 Grosvenor St, London, N6A 4V2, Ontario, Canada

  2. Barry Zochodne and Amandine HL Truong: Equal contribution made by B Zochodne and AHL Truong

Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Cancer Biology Research, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, S-Wing, Toronto, Ontario, M4N 3M5, Canada

    Barry Zochodne, Amandine HL Truong, Kendra Stetler, Rachel R Higgins, Dan Dumont & Yaacov Ben-David

  2. Department of Immunology, University of Toronto, Arthritis and Immune Disorder Network, University Health Network, 620 University Avenue, Suite 700, Toronto, M5G 2M9, Ontario, Canada

    Stuart A Berger

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Zochodne, B., Truong, A., Stetler, K. et al. Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia. Oncogene 19, 2296–2304 (2000). https://doi.org/10.1038/sj.onc.1203590

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