Skip to main content
SpringerLink
Log in

Deciphering the Intracellular Signaling of Erythropoietin in Neuronal Cells

  • Protocol
  • First Online:
Tissue-Protective Cytokines

Part of the book series: Methods in Molecular Biology ((MIMB,volume 982))

Abstract

The search for potential drugs to treat neurodegenerative diseases has been intense in the last two decades. Among many candidates, erythropoietin (EPO) was identified as a potent protectant of neurons suffering from various adverse conditions. A wide array of literature indicates that endogenous or exogenous recombinant human erythropoietin and its variants activate cell signaling that initiates survival-promoting events in neurons and neuronal cells. This chapter gives an overview of the pro-survival signaling induced by endogenous and exogenous erythropoietin in vitro and in vivo and provides methods to further investigate the intracellular signaling. It is important to know that EPO is neuroprotective, but it will greatly enhance our chances to establish EPO as a new drug candidate if we know how EPO protects neurons.

The descriptions below summarize our current knowledge in non-neuronal and neuronal signaling pathways induced by EPO. The signaling pathways involved in EPO are multiple; some are well known whereas others are still under intense investigation and few are observed in very specific cell types. It is important to note that neuronal signaling events triggered by EPO are still incomplete and require further research. Therefore, excellent review articles that explore specific EPO-signaling events are referenced.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Davis JM, Arakawa T, Strickland TW, Yphantis DA (1987) Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry 26(9):2633–2638

    Article  PubMed  CAS  Google Scholar 

  2. Yoon D, Ponka P, Prchal JT (2011) Hypoxia. 5. Hypoxia and hematopoiesis. Am J Physiol Cell Physiol 300(6):C1215–C1222. doi:10.1152/ajpcell.00044.2011

    Article  PubMed  CAS  Google Scholar 

  3. Arcasoy MO (2008) The non-haematopoietic biological effects of erythropoietin. Br J Haematol 141(1):14–31. doi:10.1111/j.1365-2141.2008.07014.x

    Article  PubMed  CAS  Google Scholar 

  4. Juul SE, Stallings SA, Christensen RD (1999) Erythropoietin in the cerebrospinal fluid of neonates who sustained CNS injury. Pediatr Res 46(5):543–547

    Article  PubMed  CAS  Google Scholar 

  5. Fu A, Hui EK, Lu JZ, Boado RJ, Pardridge WM (2010) Neuroprotection in stroke in the mouse with intravenous erythropoietin-Trojan horse fusion protein. Brain Res 1369:203–207. doi:S0006-8993(10)02440-6 (pii) 10.1016/j.brainres.2010.10.097

    Google Scholar 

  6. Kapitsinou PP, Liu Q, Unger TL, Rha J, Davidoff O, Keith B, Epstein JA, Moores SL, Erickson-Miller CL, Haase VH (2010) Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 116(16):3039–3048. doi:10.1182/blood-2010-02-270322

    Article  PubMed  CAS  Google Scholar 

  7. Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF (1993) Structure, function, and activation of the erythropoietin receptor. Blood 81(9):2223–2236

    PubMed  CAS  Google Scholar 

  8. Watowich SS (2011) The erythropoietin receptor: molecular structure and hematopoietic signaling pathways. J Investig Med. doi:10.231/JIM.0b013e31820fb28c

  9. Jelkmann W (2004) Molecular biology of erythropoietin. Intern Med 43(8):649–659

    Article  PubMed  CAS  Google Scholar 

  10. Ghezzi P, Bernaudin M, Bianchi R, Blomgren K, Brines M, Campana W, Cavaletti G, Cerami A, Chopp M, Coleman T, Digicaylioglu M, Ehrenreich H, Erbayraktar S, Erbayraktar Z, Gassmann M, Genc S, Gokmen N, Grasso G, Juul S, Lipton SA, Hand CC, Latini R, Lauria G, Leist M, Newton SS, Petit E, Probert L, Sfacteria A, Siren AL, Talan M, Thiemermann C, Westenbrink D, Yaqoob M, Zhu C (2010) Erythropoietin: not just about erythropoiesis. Lancet 375(9732):2142. doi:10.1016/S0140-6736(10)60992-0

    Article  PubMed  Google Scholar 

  11. Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN (1993) JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74(2):227–236

    Article  PubMed  CAS  Google Scholar 

  12. Chateauvieux S, Grigorakaki C, Morceau F, Dicato M, Diederich M (2011) Erythropoietin, erythropoiesis and beyond. Biochem Pharmacol. doi:10.1016/j.bcp.2011.06.045

  13. Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF (2001) Ineffective erythropoiesis in Stat5a(−/−)5b(−/−) mice due to decreased survival of early erythroblasts. Blood 98(12):3261–3273

    Article  PubMed  CAS  Google Scholar 

  14. Koury MJ, Bondurant MC (1991) The mechanism of erythropoietin action. Am J Kidney Dis 18(4 Suppl 1):20–23

    PubMed  CAS  Google Scholar 

  15. Simon MC, Pevny L, Wiles MV, Keller G, Costantini F, Orkin SH (1992) Rescue of erythroid development in gene targeted GATA-1- mouse embryonic stem cells. Nat Genet 1(2):92–98. doi:10.1038/ng0592-92

    Article  PubMed  CAS  Google Scholar 

  16. Lei H, Quelle FW (2009) FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage. Mol Cancer Res 7(8):1294–1303. doi:10.1158/1541-7786.MCR-08-0531

    Article  PubMed  CAS  Google Scholar 

  17. Kashii Y, Uchida M, Kirito K, Tanaka M, Nishijima K, Toshima M, Ando T, Koizumi K, Endoh T, Sawada K, Momoi M, Miura Y, Ozawa K, Komatsu N (2000) A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of ­phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction. Blood 96(3):941–949

    PubMed  CAS  Google Scholar 

  18. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281(5381):1312–1316

    Article  PubMed  CAS  Google Scholar 

  19. Marti HH, Wenger RH, Rivas LA, Straumann U, Digicaylioglu M, Henn V, Yonekawa Y, Bauer C, Gassmann M (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8(4):666–676

    Article  PubMed  CAS  Google Scholar 

  20. Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19(6):643–651. doi:10.1097/00004647-199906000-00007

    Article  PubMed  CAS  Google Scholar 

  21. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R (1994) A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269(30):19488–19493

    PubMed  CAS  Google Scholar 

  22. Liu C, Shen K, Liu Z, Noguchi CT (1997) Regulated human erythropoietin receptor expression in mouse brain. J Biol Chem 272(51):32395–32400

    Article  PubMed  CAS  Google Scholar 

  23. Tsai PT, Ohab JJ, Kertesz N, Groszer M, Matter C, Gao J, Liu X, Wu H, Carmichael ST (2006) A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci 26(4):1269–1274. doi:10.1523/JNEUROSCI.4480-05.2006

    Article  PubMed  CAS  Google Scholar 

  24. Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML (1999) Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development 126(16):3597–3605

    PubMed  CAS  Google Scholar 

  25. Digicaylioglu M, Bichet S, Marti HH, Wenger RH, Rivas LA, Bauer C, Gassmann M (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci U S A 92(9):3717–3720

    Article  PubMed  CAS  Google Scholar 

  26. Baciu I, Oprisiu C, Derevenco P, Vasile V, Muresan A, Hriscu M, Chis I (2000) The brain and other sites of erythropoietin production. Rom J Physiol 37(1–4):3–14

    PubMed  CAS  Google Scholar 

  27. Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H (2001) Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol 101(3):271–276

    PubMed  CAS  Google Scholar 

  28. Sugawa M, Sakurai Y, Ishikawa-Ieda Y, Suzuki H, Asou H (2002) Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neurosci Res 44(4):391–403

    Article  PubMed  CAS  Google Scholar 

  29. Weidemann A, Kerdiles YM, Knaup KX, Rafie CA, Boutin AT, Stockmann C, Takeda N, Scadeng M, Shih AY, Haase VH, Simon MC, Kleinfeld D, Johnson RS (2009) The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest 119(11):3373–3383. doi:10.1172/JCI39378

    PubMed  CAS  Google Scholar 

  30. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116(1):201–211

    PubMed  CAS  Google Scholar 

  31. Hensey C, Gautier J (1998) Programmed cell death during Xenopus development: a spatio-temporal analysis. Dev Biol 203(1):36–48. doi:10.1006/dbio.1998.9028

    Article  PubMed  CAS  Google Scholar 

  32. Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412(6847):641–647. doi:10.1038/35088074, 35088074 (pii)

    Article  PubMed  CAS  Google Scholar 

  33. Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci U S A 96(14):8212–8216

    Article  PubMed  CAS  Google Scholar 

  34. Budd SL, Lipton SA (1999) Signaling events in NMDA receptor-induced apoptosis in cerebrocortical cultures. Ann N Y Acad Sci 893:261–264

    Article  PubMed  CAS  Google Scholar 

  35. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 92(16):7162–7166

    Article  PubMed  CAS  Google Scholar 

  36. D’Emilia DM, Lipton SA (1999) Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neurosci Lett 265(2):103–106

    Article  PubMed  Google Scholar 

  37. Nicotera P, Ankarcrona M, Bonfoco E, Orrenius S, Lipton SA (1997) Neuronal necrosis and apoptosis: two distinct events induced by exposure to glutamate or oxidative stress. Adv Neurol 72:95–101

    PubMed  CAS  Google Scholar 

  38. Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D’Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA (2002) Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J Neurosci 22(10):4015–4024. doi:20026351

    PubMed  CAS  Google Scholar 

  39. Sinclair AM, Coxon A, McCaffery I, Kaufman S, Paweletz K, Liu L, Busse L, Swift S, Elliott S, Begley CG (2010) Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood 115(21):4264–4272. doi:10.1182/blood-2009-10-248666

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Neurosurgery and Physiology, University of Texas Health Science Center, San Antonio, TX, USA

    Murat Digicaylioglu

Authors
  1. Murat Digicaylioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Medical School, Brighton and Sussex, Trafford Centre, Falmer, BN1 9RY, United Kingdom

    Pietro Ghezzi

  2. Leiden University Medical Center, Stille Rijn 11a, Leiden, 2312 DE, Netherlands

    Anthony Cerami

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Digicaylioglu, M. (2013). Deciphering the Intracellular Signaling of Erythropoietin in Neuronal Cells. In: Ghezzi, P., Cerami, A. (eds) Tissue-Protective Cytokines. Methods in Molecular Biology, vol 982. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-308-4_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-308-4_11

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-307-7

  • Online ISBN: 978-1-62703-308-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation