Signaling and Stem Cells
Induction of Signalling in Non-Erythroid Cells by Pharmacological Levels of ErythropoietinDunlop E.A.a · Percy M.J.b · Boland M.P.a · Maxwell A.P.c · Lappin T.R.a
aCentre for Cancer Research and Cell Biology, Queen’s University Belfast, bHaematology Department, and cNephrology Research Group, Belfast City Hospital, Belfast, UK
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Erythropoiesis is maintained by the hormone erythropoietin (Epo) binding to its cognate receptor (EpoR) on erythroid progenitor cells. The Epo-EpoR interaction initiates a signal transduction process that regulates the survival, growth and differentiation of these cells. Originally perceived as highly lineage-restricted, Epo is now recognised to have pleiotropic effects extending beyond the maintenance of red cell mass. Functional interactions between Epo and EpoR have been demonstrated in numerous cells and tissues. EpoR expression on neoplastic cells leads to concern that recombinant human erythropoietin, used to treat anaemia in cancer patients, may augment tumour growth. Here we demonstrate that EPO, at pharmacological concentrations, can activate three major signalling cascades, viz. the Jak2/STAT5, Ras/ERK and PI3K/Akt pathways in non-small cell lung carcinoma (NSCLC) cell lines. EpoR synthesis is normally under the control of GATA-1, but NSCLC cells exhibit decreased GATA-1 levels compared to GATA-2, -3 and -6, suggesting that GATA-1 is not essential for EpoR production. The increased Epo-induced signalling was not associated with a growth advantage for the NSCLC cells.
© 2006 S. Karger AG, Basel
- Tan CC, Eckardt KU, Ratcliffe PJ: Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int 1991;40:69–76.
- Lappin TR, Maxwell AP, Johnston PG: EPO’s alter ego: erythropoietin has multiple actions. Stem Cells 2002;20:485–492.
- Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E: Structural characterization of human erythropoietin. J Biol Chem 1986;261:3116–3121.
- Sasaki H, Bothner B, Dell A, Fukuda M: Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem 1987;262:12059–12076.
- Jones SS, D’Andrea AD, Haines LL, Wong GG: Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood 1990;76:31–35.
- Winkelmann JC, Penny LA, Deaven LL, Forget BG, Jenkins RB: The gene for the human erythropoietin receptor: analysis of the coding sequence and assignment to chromosome 19p. Blood 1990;76:24–30.
- Chin K, Yu X, Beleslin-Cokic B, Liu C, Shen K, Mohrenweiser HW, Noguchi CT: Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res 2000;81:29–42.
- Lin CS, Lim SK, D’Agati V, Costantini F: Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 1996;10:154–164.
- Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML: Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development 1999;126:3597–3605.
- Juul SE, Yachnis AT, Christensen RD: Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early Hum Dev 1998;52:235–249.
- Juul SE, Yachnis AT, Rojiani AM, Christensen RD: Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol 1999;2:148–158.
- Masuda S, Nagao M, Takahata K, Konishi Y, Gallyas F Jr, Tabira T, Sasaki R: Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 1993;268:11208–11216.
- Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R: Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 1997;76:105–116.
- Anagnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N, Noguchi CT: Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 1994;91:3974–3978.
- Ribatti D, Presta M, Vacca A, Ria R, Giuliani R, Dell’Era P, Nico B, Roncali L, Dammacco F: Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 1999;93:2627–2636.
- Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT, Noguchi CT: Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem 2000;275:39754–39761.
- Mioni R, Gottardello F, Bordon P, Montini G, Foresta C: Evidence for specific binding and stimulatory effects of recombinant human erythropoietin on isolated adult rat Leydig cells. Acta Endocrinol (Copenh) 1992;127:459–465.
- Fraser JK, Tan AS, Lin FK, Berridge MV: Expression of specific high-affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 1989;17:10–16.
- Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, Verma A: Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001;61:3561–3565.
- Westenfelder C, Baranowski RL: Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int 2000;58:647–657.
- Selzer E, Wacheck V, Kodym R, Schlagbauer-Wadl H, Schlegel W, Pehamberger H, Jansen B: Erythropoietin receptor expression in human melanoma cells. Melanoma Res 2000;10:421–426.
- Thompson A, Quinn MF, Grimwade D, O’Neill CM, Ahmed MR, Grimes S, McMullin MF, Cotter F, Lappin TRJ: Global down-regulation of HOX gene expression in PML-RARα+ acute promyelocytic leukemia identified by small-array real-time PCR. Blood 2003;101:1558–1565.
- Westphal G, Niederberger E, Blum C, Wollman Y, Knoch TA, Rebel W, Debus J, Friedrich E: Erythropoietin and G-CSF receptors in human tumor cells: expression and aspects regarding functionality. Tumori 2002;88:150–159.
- Elliott S, Busse L, Bass MB, Lu H, Sarosi I, Sinclair AM, Spahr C, Um M, Van G, Begley G: Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006;107:1892–1895.
- Buemi M, Caccamo C, Nostro L, Cavallaro E, Floccari F, Grasso G: Brain and cancer: the protective role of erythropoietin. Med Res Rev 2005;25:245–259.
- Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P: Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 2001;98:4044–4049.
- Chin K, Oda N, Shen K, Noguchi CT: Regulation of transcription of the human erythropoietin receptor gene by proteins binding to GATA-1 and Sp1 motifs. Nucleic Acids Res 1995;23:3041–3049.
- Orkin SH: GATA-binding transcription factors in hematopoietic cells. Blood 1992;80:575–581.
- Tsarovina K, Pattyn A, Stubbusch J, Muller F, van der Wees J, Schneider C, Brunet JF, Rohrer H: Essential role of Gata transcription factors in sympathetic neuron development. Development 2004;131:4775–4786.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.