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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/12/21 23:28:04」(JST)

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This article is about the endogenous erythropoietin protein. For the erythropoietin drug, see Epoetin alfa.

Erythropoietin, also known as erythropoetin or erthropoyetin (/ɨˌrɪθrɵˈpɔɪ.ɨtɨn/, /ɨˌrɪθrɵˈpɔɪtən/, and /ɨˌriːθrɵ-/) or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34,000.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and tubular epithelial cells. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. Erythropoietin is the hormone that regulates red blood cell production. It also has other known biological functions. For example, erythropoietin plays an important role in the brain's response to neuronal injury.^[1] EPO is also involved in the wound healing process.^[2]

When exogenous EPO is used as a performance-enhancing drug, it is classified as an erythropoiesis-stimulating agent (ESA). Exogenous EPO can often be detected in blood, due to slight difference from the endogenous protein, for example in features of posttranslational modification.

Function

Primary role in red blood cell production

Erythropoietin is an essential hormone for red cell production. Without it, definitive erythropoiesis, the process of red cell production, does not take place. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E, pro-erythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in the bone marrow in humans) by promoting their survival through protecting these cells from apoptosis.

Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., IL-3, IL-6, glucocorticoids, and SCF) involved in the development of erythroid lineage from multipotent progenitors. The burst forming unit-erythroid (BFU-E) cells start erythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage, the colony forming unit-erythroid (CFU-E), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the pro-erythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it.

Secondary roles

Erythropoietin has a range of actions including vasoconstriction-dependent hypertension, stimulating angiogenesis, and inducing proliferation of smooth muscle fibers. It has also been shown that erythropoietin can increase iron absorption by suppressing the hormone hepcidin.^[3]

EPO also affects neuronal protection during hypoxic conditions (stroke, etc.).^[4] Trials on human subjects are not yet reported; if proven to be a viable treatment of heart attack and stroke patients, it could improve the outcome and quality of life. The reasoning behind such a proposal is that EPO levels of 100x of the baseline have been detected in brain as a natural response to (primarily) hypoxic damage.^[5] This and other research demonstrate the role of natural hormones in the healing process. (growth hormone and oxytocin also improve healing process).^[6]

Mechanism of action

Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR).^[7]^[8]

EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around 5 hours. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections). EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signaling cascade. Erythropoietin receptor expression is found in a number of tissues such as the bone marrow and peripheral/central nervous tissue. In bloodstream, red cells themselves do not express erythropoietin receptor, and therefore cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis.

Synthesis and regulation

Erythropoietin levels in blood are quite low in the absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase a 1000-fold, reaching 10,000 mU/mL of blood. EPO is produced mainly by peritubular capillary lining cells of the renal cortex; which are highly specialized epithelial-like cells. It is synthesized by renal peritubular cells in adults, with a small amount being produced in the liver.^[9]^[10] Regulation is believed to rely on a feed-back mechanism measuring blood oxygenation.^[11] Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors (HIFs), are hydroxylated and proteosomally digested in the presence of oxygen.

Medical uses

Main article: Epoetin alfa

Erythropoietins available for use as therapeutic agents are produced by recombinant DNA technology in cell culture, and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating anemia resulting from chronic kidney disease and myelodysplasia from the treatment of cancer (chemotherapy and radiation), but include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, tumor recurrence, and other severe off target effects.^[12]

Available forms

Recombinant EPO has a variety of glycosylation patterns giving rise to alfa, beta, delta, and omega forms:

epoetin alfa: Darbepoetin (Aranesp)^[13] Epocept (Lupin pharma) Nanokine (Nanogen Pharmaceutical biotechnology, Vietnam Epofit (Intas pharma) Epogen, made by Amgen Epogin Eprex, made by Janssen-Cilag Procrit^[14] epoetin beta: NeoRecormon, made by Hoffmann–La Roche Recormon Methoxy polyethylene glycol-epoetin beta (Mircera) by Roche epoetin delta: Dynepo trademark name for an erythropoiesis stimulating protein, by Shire plc epoetin omega: Epomax	epoetin zeta (biosimilar forms for epoetin apha): Silapo (Stada) Retacrit (Hospira) Miscellaneous: Epocept, made by Lupin Pharmaceuticals EPOTrust, made by Panacea Biotec Ltd Erypro Safe, made by Biocon Ltd. Repoitin, made by Serum Institute of India Limited Vintor, made by Emcure Pharmaceuticals Epofit, made by Intas pharma Erykine, made by Intas Biopharmaceutica Wepox, made by Wockhardt Biotech Espogen, made by LG life sciences. ReliPoietin, made by Reliance Life Sciences Shanpoietin, made by Shantha Biotechnics Ltd Zyrop, made by Cadila Healthcare Ltd. EPIAO (rHuEPO), made by Shenyang Sunshine Pharmaceutical Co.. LTD. China

Darbepoetin alfa is a form created by 5 substitutions (Asn-57, Thr-59, Val-114, Asn-115 and Thr-117) that create 2 new N-glycosylation sites.

More recently, a novel erythropoiesis-stimulating protein (NESP) has been produced.^[15] This glycoprotein demonstrates anti-anemic capabilities and has a longer terminal half-life than erythropoietin. NESP offers chronic renal failure patients a lower dose of hormones to maintain normal hemoglobin levels.

Blood doping

ESAs have a history of use as blood doping agents in endurance sports such as horseracing, boxing,^[16] cycling, rowing, distance running, race walking, cross country skiing, biathlon, and triathlons. The overall oxygen delivery system (blood oxygen levels, as well as heart stroke volume, vascularization, and lung function) is one of the major limiting factors to muscles' ability to perform endurance exercise. Therefore, the primary reason athletes may use ESAs is to improve oxygen delivery to muscles, which directly improves their endurance capacity. With the advent of recombinant erythropoietin in the 1990s, the practice of autologous and homologous blood transfusion has been partially replaced by injecting erythropoietin such that the body naturally produces its own red cells. ESAs increase hematocrit (% of blood volume that is red cell mass) and total red cell mass in the body, providing a good advantage in sports where such practice is banned.^[17] In addition to ethical considerations in sports, providing an increased red cell mass beyond the natural levels reduces blood flow due to increased viscosity, and increases the likelihood of thrombosis and stroke. Due to dangers associated with using ESAs, their use should be limited to the clinic where anemic patients are boosted back to normal hemoglobin levels (as opposed to going above the normal levels for performance advantage, leading to an increased risk of death).

Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national anti-doping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athlete's urine.

In 2002, at the Winter Olympic Games in Salt Lake City, Dr. Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports.^[18] At the 2012 Summer Olympics in London, Alex Schwazer, the Gold medalist in the 50-kilometer race walk in the 2008 Summer Olympics in Beijing, tested positive for EPO and was disqualified.^[19]

Since 2002, EPO tests performed by U.S. sports authorities have consisted of only a urine or "direct" test. From 2000–2006, EPO tests at the Olympics were conducted on both blood and urine.^[20]^[21] However, several compounds have been identified that can be taken orally to stimulate endogenous EPO production. Most of the compounds stabilize the hypoxia inducible transcription factors (HIF) which activate the EPO gene. The compounds include oxo-glutarate competitors but also simple ions such as cobalt(II) chloride. ^[22]

Cycling

It is believed that synthetic EPO came into use in cycling about 1990.^[23] In theory, EPO use can increase VO2 max by a significant amount,^[24] making it useful for endurance sports like cycling. Italian anti-doping advocate Sandro Donati has claimed that the history of doping in cycling can be traced to the Italian Dr Francesco Conconi at the University of Ferrara. Conconi had worked on the idea of giving athletes tranfusions of their own blood in the 1980s. Donati felt this work "opened the road to EPO . . . because blood doping was a trial to understand the role of EPO".^[25]

Dr. Michele Ferrari, a former student and mentee of Conconi,^[26] had a controversial interview mentioning the drug in 1994, just after his Gewiss-Ballan team had a remarkable performance in the La Flèche Wallonne race. Ferrari told l'Equipe journalist Jean-Michel Rouet that EPO had no "fundamental" effect on performance and that if a rider used it is wouldn't "scandalize" himself. After the journalist pointed out several riders were suspected of dying from EPO, Ferrari said that EPO was not dangerous, that only abuse of it was dangerous, saying "It's also dangerous to drink 10 liters of orange juice." The 'orange juice' comment has been widely misquoted.^[27]^[28] Ferrari was fired shortly after but continued to work in the industry.^[26] That same year, Sandro Donati, working for the Italian National Olympic Committee, presented a report accusing Conconi of being linked to the use of EPO in the sport.^[25]

In 1997 the Union Cycliste Internationale (UCI) instituted a new rule that riders testing above 50% haematocrit were not allowed to race.^[29] Robert Millar, former racer, later wrote for Cycling News that the 50% limit was "was an open invitation to dope to that level", pointing out that normally haematocrit levels would start "around 40-42%" and drop during the course of a "grand tour", but after EPO they were staying at 50% for "weeks at a time".^[30]

By 1998 EPO use had become widespread and the Festina affair tarnished the 1998 Tour de France.^[23] One manager offered a 270,000 franc-per-month raise to Christophe Bassons if he would use EPO (Bassons refused).^[31]

In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout the majority of his career as a professional cyclist.^[32] In 2012 the USADA released a report on its investigation into the U.S. Postal Service cycling team and blood doping. The report contained affidavits from numerous riders on the team including Frankie Andreu, Tyler Hamilton, George Hincapie, Floyd Landis, Levi Leipheimer, and several others, outlining explicitly that they, and Lance Armstrong, used a cocktail of performance enhancing substances to fuel their success in the Tour de France, most notably, EPO, during the 1999 tour. Armstrong was consequently stripped of his seven tour wins by USADA, and the UCI subsequently concurred with this decision. Tour organisers have expunged Armstrong's name from the annals of the race's history. Witnesses testified that code words used for EPO included "Edgar", "Poe",^[33] "Edgar Allen Poe", and "Zumo" (Spanish for 'juice').^[34]

Some anti-doping cycling advocates, such as Greg LeMond and Emma O'Reilly, have claimed part of the motivation for their public speaking against doping in the sport was caused by what they believed to be doping-related deaths amongst professional cyclists.^[35]^[36]^[37] Greg LeMond has suggested establishing a baseline for VO2 Max of riders (and other attributes) to detect abnormal performance increases.^[38]

History

In 1905, Paul Carnot, a professor of medicine in Paris, France, and his assistant, Clotilde Deflandre, proposed the idea that hormones regulate the production of red blood cells. After conducting experiments on rabbits subject to bloodletting, Carnot and Deflandre attributed an increase in red blood cells in rabbit subjects to a hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto continued to study red cell production and later called the hemopoietic substance 'erythropoietin'. Further studies investigating the existence of EPO by K.R. Reissman (unknown location) and Allan J. Erslev (Thomas Jefferson Medical College) demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit. This substance was finally purified and confirmed as erythropoietin, opening doors to therapeutic uses for EPO in diseases like anemia.^[11]^[39]

Haematologist John Adamson and nephrologist Joseph W. Eschbach looked at various forms of renal failure and the role of the natural hormone EPO in the formation of red blood cells. Studying sheep and other animals in the 1970s, the two scientists helped establish that EPO stimulates the production of red cells in bone marrow and could lead to a treatment for anemia in humans. In 1968, Goldwasser and Kung began work to purify human EPO, and managed to purify milligram quantities of over 95% pure material by 1977.^[40] Pure EPO allowed the amino acid sequence to be partially identified and the gene to be isolated.^[11] Later an NIH-funded researcher at Columbia University discovered a way to synthesize EPO. Columbia University patented the technique, and licensed it to Amgen. Controversy has ensued over the fairness of the rewards that Amgen reaped from NIH-funded work, and Goldwasser was never financially rewarded for his work.^[41]

In the 1980s, Adamson, Joseph W. Eschbach, Joan C. Egrie, Michael R. Downing and Jeffrey K. Browne conducted a clinical trial at the Northwest Kidney Centers for a synthetic form of the hormone, Epogen, produced by Amgen. The trial was successful, and the results were published in the New England Journal of Medicine in January 1987.^[42]

In 1985, Lin et al. isolated the human erythropoietin gene from a genomic phage library and were able to characterize it for research and production.^[43] Their research demonstrated that the gene for erythropoietin encoded the production of EPO in mammalian cells that is biologically active in vitro and in vivo. The industrial production of recombinant human erythropoietin (RhEpo) for treating anemia patients would begin soon after.

In 1989, the U.S. Food and Drug Administration approved the hormone, called Epogen, which remains in use today.

References

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^ Haroon ZA, Amin K, Jiang X, Arcasoy MO (September 2003). "A novel role for erythropoietin during fibrin-induced wound-healing response". Am. J. Pathol. 163 (3): 993–1000. doi:10.1016/S0002-9440(10)63459-1. PMC 1868246. PMID 12937140. http://ajp.amjpathol.org/cgi/content/abstract/163/3/993.
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^ Jacobson LO, Goldwasser E, Fried W, Plzak L (March 1957). "Role of the kidney in erythropoiesis". Nature 179 (4560): 633–4. doi:10.1038/179633a0. PMID 13418752.
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^ "Aranesp(darbepoetin alfa)". Amgen.com. http://www.aranesp.com/. Retrieved 2009-04-29.
^ "Procrit (Epoetin alfa)". Ortho Biotech Products. Archived from the original on 2009-10-26. http://web.archive.org/web/20091026055514/http://www.procrit.com/procrit/. Retrieved 2009-04-29.
^ Macdougall IC (July 2000). "Novel erythropoiesis stimulating protein". Semin. Nephrol. 20 (4): 375–81. PMID 10928340.
^ "Boxing Scandals". Bleacher Report. 2011-12. http://bleacherreport.com/articles/965780-13-most-shocking-scandals-in-boxing-history#/articles/965780-13-most-shocking-scandals-in-boxing-history/page/5. Retrieved 2011-12-22.
^ Jelkmann W, Lundby C (September 2011). "Blood doping and its detection". Blood. 118 (9): 2395-404. PMID 21652677.
^ Steeg JL (2007-02-28). "Catlin has made a career out of busting juicers - USATODAY.com". USA TODAY. http://www.usatoday.com/sports/olympics/2007-02-28-catlin-drug-lab_N.htm. Retrieved 2009-03-31.
^ "Ousted Olympic race walk champion says he bought EPO in Turkey, hid it in refrigerator at home"^{[dead link]} Associated Press story in the Washington Post (August 8, 2012)
^ Lasne F, Martin L, Crepin N, de Ceaurriz J (December 2002). "Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones". Anal. Biochem. 311 (2): 119–26. doi:10.1016/S0003-2697(02)00407-4. PMID 12470670.
^ Kohler M, Ayotte C, Desharnais P, Flenker U, Lüdke S, Thevis M, Völker-Schänzer E, Schänzer W (January 2008). "Discrimination of recombinant and endogenous urinary erythropoietin by calculating relative mobility values from SDS gels". Int J Sports Med 29 (1): 1–6. doi:10.1055/s-2007-989369. PMID 18050057.
^ W. Jelkmann: The disparate roles of cobalt in erythropoiesis, and doping relevance. Open Journal of Hematology, 2012, 3-6. http://rossscience.org/ojhmt/2075-907X-3-6.php
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^ ^a ^b Harrison C (2003-03-01). "The Man Who Knows Too Much". Sport Monthly. chrisharrisonwriting. http://www.chrisharrisonwriting.com/journalism/_3/.
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^ Maloney T (2003). "An Interview With Dr. Michele Ferrari, part two: That l'Equipe Interview". by Jean-Michel Rouet, from l'Equipe, 1994, reprinted excerpt. Cycling News. http://autobus.cyclingnews.com/riders/2003/interviews/?id=ferrari03b#equipe.
^ 10 liters of orange juice: see the article on Water intoxication, for example.
^ Martin DT, Ashenden M, Parisotto R, Pyne D, Hahn AG (March–April 1997). "Blood testing for professional cyclists: What's a fair hematocrit limit?". Sports Science. http://www.sportsci.org/news/news9703/AISblood.html.
^ Millar R (2003-10-23). "The Bare Minimum". Cycling News. http://www.cyclingnews.com/blogs/robert-millar/the-bare-minimum.
^ Startt J (2012-10-15). "Christophe Bassons Interview: 'People Now See I Wasn't Lying'". This Just In. Bicycling.com. http://bicycling.com/blogs/thisjustin/2012/10/15/bassons-people-now-see-i-wasn%E2%80%99t-lying/.
^ "Landis admits to illegal drug use". BBC News. 2010-05-20. http://news.bbc.co.uk/sport2/hi/other_sports/cycling/8694452.stm.
^ "U.S. Postal Service Pro Cycling Team Investigation". Statement From USADA CEO Travis T. Tygart Regarding The U.S. Postal Service Pro Cycling Team Doping Conspiracy. USADA. 2012-10-10. http://cyclinginvestigation.usada.org/.
^ Chapman M (2012-10-15). "Cycling's Dirty Truth". Sport, Peddlers. BBC Radio 5. http://www.bbc.co.uk/programmes/b01ngqxd+.
^ "Greg LeMond - 'Cycling is dying through Drugs' at Play the Game Conference" (video). YouTube. 2009-06-12. http://www.youtube.com/watch?v=wDy5NLVkliU&feature=related+.
^ "Cycling is dying through drugs" (video). Blog Archive. Coventry University Podcasts. 2009-06-12. http://coventryuniversity.podbean.com/2009/06/12/greg-lemond-cycling-is-dying-through-drugs/+.
^ "Emma OReilly Affidavit" (pdf). U.S. Postal Service Pro Cycling Team Investigation. USADA. 2012-10-09. http://d3epuodzu3wuis.cloudfront.net/OReilly%2c+Emma+Affidavit.pdf.
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^ Ahmet Höke (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 0-387-30010-4. OCLC 64571745. http://books.google.com/?id=A76u7g0QnskC.
^ Miyake T; Kung, CK; Goldwasser, E (Aug 1997). "Purification of human erythropoietin". J. Biol. Chem. 252 (15): 5558–5564. PMID 18467. http://www.jbc.org/content/252/15/5558.long.
^ Angell, Marcia (2005). The Truth About the Drug Companies : How They Deceive Us and What to Do About It. New York: Random House Trade Paperbacks. p. 60. ISBN 0-375-76094-6.
^ Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". N. Engl. J. Med. 316 (2): 73–8. doi:10.1056/NEJM198701083160203. PMID 3537801.
^ Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (November 1985). "Cloning and expression of the human erythropoietin gene". Proc. Natl. Acad. Sci. U.S.A. 82 (22): 7580–4. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178. http://www.pnas.org/content/82/22/7580.abstract.

External links

NYT - 1987 announcement of Epogen's clinical success

English Journal

Interview: Partnering with the industry: the Olympic laboratory model.

Cowan DA, Barker CP.SourceDepartment of Forensic Science & Drug Monitoring, King's College London, 150 Stamford Street, London, SE1 9NH, UK. david.a.cowan@kcl.ac.uk.
Bioanalysis.Bioanalysis.2012 Jul;4(13):1545-8.
David A Cowan and Campbell P Barker speak to Ryan De Vooght-Johnson at Bioanalysis in May 2012 about the partnership between industry and academia for the setup and running of the doping-control laboratory for the London 2012 Olympic Games. David A Cowan is Director of the London 2012 anti-doping
PMID 22831471

A harm reduction paradox: Comparing China's policies on needle and syringe exchange and methadone maintenance.

Smith K, Bartlett N, Wang N.SourceDepartment of Epidemiology, University of North Carolina, Chapel Hill, N.C., USA; National Center for AIDS/STD Control and Prevention, Beijing, China.
The International journal on drug policy.Int J Drug Policy.2012 Jul;23(4):327-32. Epub 2012 Feb 28.
BACKGROUND: China has launched methadone maintenance treatment (MMT) and needle and syringe exchange programmes (NSEP) as part of the country's HIV prevention strategy amongst injection drug users. MMT is expanding, with backing from multiple government ministries, however, NSEP have received less p
PMID 22377341

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リンク元	「novel erythropoietin-stimulating protein」
関連記事	「NES」「NE」

「novel erythropoietin-stimulating protein」

Erythropoietin
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1BUY, 1CN4, 1EER
Identifiers
Symbols	EPO; EP; MVCD2
External IDs	OMIM: 133170 MGI: 95407 HomoloGene: 624 ChEMBL: 5837 GeneCards: EPO Gene
Gene Ontology
Molecular function	• erythropoietin receptor binding; • hormone activity; • protein binding; • protein kinase activator activity; • eukaryotic cell surface binding;
Cellular component	• extracellular region; • extracellular space;
Biological process	• apoptotic process; • signal transduction; • embryo implantation; • aging; • blood circulation; • positive regulation of cell proliferation; • response to salt stress; • negative regulation of sodium ion transport; • peptidyl-serine phosphorylation; • negative regulation of ion transmembrane transporter activity; • response to lipopolysaccharide; • response to vitamin A; • cellular response to stress; • response to testosterone stimulus; • positive regulation of tyrosine phosphorylation of Stat5 protein; • hemoglobin biosynthetic process; • negative regulation of apoptotic process; • erythrocyte maturation; • response to estrogen stimulus; • positive regulation of neuron differentiation; • positive regulation of DNA replication; • positive regulation of transcription, DNA-dependent; • positive regulation of Ras protein signal transduction; • response to axon injury; • response to electrical stimulus; • response to hyperoxia; • regulation of transcription from RNA polymerase II promoter in response to hypoxia; • response to interleukin-1; • cellular response to hypoxia; • cellular hyperosmotic response;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

同: NESP
関: darbepo- etin al fa

「NES」

　　[★]

核外移行シグナル、核外輸送シグナル

関: nuclear export signal

「NE」

　　[★] ノルエピネフリン norepinephrine 　

[USA_2001-1] Siren AL et al. (2001). "Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress". Proc Natl Acad Sci USA 98 (7): 4044–4049. doi:10.1073/pnas.051606598. PMC 31176. PMID 11259643. //www.ncbi.nlm.nih.gov/pmc/articles/PMC31176/.

[pmid12937140-2] Haroon ZA, Amin K, Jiang X, Arcasoy MO (September 2003). "A novel role for erythropoietin during fibrin-induced wound-healing response". Am. J. Pathol. 163 (3): 993–1000. doi:10.1016/S0002-9440(10)63459-1. PMC 1868246. PMID 12937140. http://ajp.amjpathol.org/cgi/content/abstract/163/3/993.

[hepcidin-3] Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman R, Maxwell PH, Choi P (March 2010). "Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin". Haematologica 95 (3): 505–8. doi:10.3324/haematol.2009.013136. PMC 2833083. PMID 19833632. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2833083/.

[pmid11259643-4] Sirén 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 (March 2001). "Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 4044–9. doi:10.1073/pnas.051606598. PMC 31176. PMID 11259643. //www.ncbi.nlm.nih.gov/pmc/articles/PMC31176/.

[pmid9027715-5] Marti HH, Gassmann M, Wenger RH, Kvietikova I, Morganti-Kossmann MC, Kossmann T, Trentz O, Bauer C (February 1997). "Detection of erythropoietin in human liquor: intrinsic erythropoietin production in the brain". Kidney Int. 51 (2): 416–8. doi:10.1038/ki.1997.55. PMID 9027715.

[pmid20144509-6] Gouin JP, Carter CS, Pournajafi-Nazarloo H, Glaser R, Malarkey WB, Loving TJ, Stowell J, Kiecolt-Glaser JK (August 2010). "Marital behavior, oxytocin, vasopressin, and wound healing". Psychoneuroendocrinology 35 (7): 1082–90. doi:10.1016/j.psyneuen.2010.01.009. PMC 2888874. PMID 20144509. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2888874/.

[pmid10318834-7] Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK (May 1999). "Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide". J. Biol. Chem. 274 (20): 14163–9. doi:10.1074/jbc.274.20.14163. PMID 10318834.

[pmid9808045-8] Livnah O, Johnson DL, Stura EA, Farrell FX, Barbone FP, You Y, Liu KD, Goldsmith MA, He W, Krause CD, Pestka S, Jolliffe LK, Wilson IA (November 1998). "An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation". Nat. Struct. Biol. 5 (11): 993–1004. doi:10.1038/2965. PMID 9808045.

[Jacobson1957-9] Jacobson LO, Goldwasser E, Fried W, Plzak L (March 1957). "Role of the kidney in erythropoiesis". Nature 179 (4560): 633–4. doi:10.1038/179633a0. PMID 13418752.

[Fisher1996-10] Fisher JW, Koury S, Ducey T, Mendel S (October 1996). "Erythropoietin production by interstitial cells of hypoxic monkey kidneys". British journal of haematology 95 (1): 27–32. doi:10.1046/j.1365-2141.1996.d01-1864.x. PMID 8857934.

[pmid17253966-11] Jelkmann, W (2007). "Erythropoietin after a century of research: younger than ever". Eur J Haematol. 78 (3): 183–205. doi:10.1111/j.1600-0609.2007.00818.x. PMID 17253966.

[url_Epogen_Procrit__FDA-12] "Safety Labeling Changes: Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa)". MedWatch: The FDA Safety Information and Adverse Event Reporting Program. United States Food and Drug Administration. 2011-08-11. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm267698.htm.

[urlAranesp.28darbepoetin_alfa.29-13] "Aranesp(darbepoetin alfa)". Amgen.com. http://www.aranesp.com/. Retrieved 2009-04-29.

[urlProcrit-14] "Procrit (Epoetin alfa)". Ortho Biotech Products. Archived from the original on 2009-10-26. http://web.archive.org/web/20091026055514/http://www.procrit.com/procrit/. Retrieved 2009-04-29.

[pmid10928340-15] Macdougall IC (July 2000). "Novel erythropoiesis stimulating protein". Semin. Nephrol. 20 (4): 375–81. PMID 10928340.

[The_13_most_shocking_scandals_in_boxing_history.-16] "Boxing Scandals". Bleacher Report. 2011-12. http://bleacherreport.com/articles/965780-13-most-shocking-scandals-in-boxing-history#/articles/965780-13-most-shocking-scandals-in-boxing-history/page/5. Retrieved 2011-12-22.

[pmid21652677-17] Jelkmann W, Lundby C (September 2011). "Blood doping and its detection". Blood. 118 (9): 2395-404. PMID 21652677.

[urlCatlin_has_made_a_career_out_of_busting_juicers_-_USATODAY.com-18] Steeg JL (2007-02-28). "Catlin has made a career out of busting juicers - USATODAY.com". USA TODAY. http://www.usatoday.com/sports/olympics/2007-02-28-catlin-drug-lab_N.htm. Retrieved 2009-03-31.

[19] "Ousted Olympic race walk champion says he bought EPO in Turkey, hid it in refrigerator at home"^{[dead link]} Associated Press story in the Washington Post (August 8, 2012)

[pmid12470670-20] Lasne F, Martin L, Crepin N, de Ceaurriz J (December 2002). "Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones". Anal. Biochem. 311 (2): 119–26. doi:10.1016/S0003-2697(02)00407-4. PMID 12470670.

[pmid18050057-21] Kohler M, Ayotte C, Desharnais P, Flenker U, Lüdke S, Thevis M, Völker-Schänzer E, Schänzer W (January 2008). "Discrimination of recombinant and endogenous urinary erythropoietin by calculating relative mobility values from SDS gels". Int J Sports Med 29 (1): 1–6. doi:10.1055/s-2007-989369. PMID 18050057.

[22] W. Jelkmann: The disparate roles of cobalt in erythropoiesis, and doping relevance. Open Journal of Hematology, 2012, 3-6. http://rossscience.org/ojhmt/2075-907X-3-6.php

[Lodewijkx_Brouwer_2011-23] Lodewijkx HF, Brouwer B (December 2011). "Some empirical notes on the epo epidemic in professional cycling". Res Q Exerc Sport 82 (4): 740–54. PMID 22276416.

[pmid18535134-24] Lundby C, Robach P, Boushel R, Thomsen JJ, Rasmussen P, Koskolou M, Calbet JA (August 2008). "Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport?". J. Appl. Physiol. 105 (2): 581–7. doi:10.1152/japplphysiol.90484.2008. PMID 18535134.

[Harrison_2003-25] Harrison C (2003-03-01). "The Man Who Knows Too Much". Sport Monthly. chrisharrisonwriting. http://www.chrisharrisonwriting.com/journalism/_3/.

[bicycling1-26] Gifford B (Jan/Feb 2006). "Paging Doctor Ferrari". Bicycling: 50–59. http://books.google.com/books?id=M8UDAAAAMBAJ&pg=PA54&lpg=PA54&dq=university+of+ferrara+conconi+ferrari&source=bl&ots=bgkYjnVtB8&sig=kMjUB-p2hcT6QbP9R787J_mLGWU&hl=en&sa=X&ei=zAGEUNWPO4mj2QXJv4CQBw&ved=0CDoQ6AEwBA#v=onepage&q=university%20of%20ferrara%20conconi%20ferrari&f=false.

[url_cyclingnews_Maloney-27] Maloney T (2003). "An Interview With Dr. Michele Ferrari, part two: That l'Equipe Interview". by Jean-Michel Rouet, from l'Equipe, 1994, reprinted excerpt. Cycling News. http://autobus.cyclingnews.com/riders/2003/interviews/?id=ferrari03b#equipe.

[28] 10 liters of orange juice: see the article on Water intoxication, for example.

[Martin_1997-29] Martin DT, Ashenden M, Parisotto R, Pyne D, Hahn AG (March–April 1997). "Blood testing for professional cyclists: What's a fair hematocrit limit?". Sports Science. http://www.sportsci.org/news/news9703/AISblood.html.

[url_cyclingnews_Millar-30] Millar R (2003-10-23). "The Bare Minimum". Cycling News. http://www.cyclingnews.com/blogs/robert-millar/the-bare-minimum.

[url_Pro_Cycling_News-31] Startt J (2012-10-15). "Christophe Bassons Interview: 'People Now See I Wasn't Lying'". This Just In. Bicycling.com. http://bicycling.com/blogs/thisjustin/2012/10/15/bassons-people-now-see-i-wasn%E2%80%99t-lying/.

[32] "Landis admits to illegal drug use". BBC News. 2010-05-20. http://news.bbc.co.uk/sport2/hi/other_sports/cycling/8694452.stm.

[urlCycling_Investigation_-_USADA-33] "U.S. Postal Service Pro Cycling Team Investigation". Statement From USADA CEO Travis T. Tygart Regarding The U.S. Postal Service Pro Cycling Team Doping Conspiracy. USADA. 2012-10-10. http://cyclinginvestigation.usada.org/.

[url_BBC_Radio_5-34] Chapman M (2012-10-15). "Cycling's Dirty Truth". Sport, Peddlers. BBC Radio 5. http://www.bbc.co.uk/programmes/b01ngqxd+.

[url_Greg_LeMond_YouTube-35] "Greg LeMond - 'Cycling is dying through Drugs' at Play the Game Conference" (video). YouTube. 2009-06-12. http://www.youtube.com/watch?v=wDy5NLVkliU&feature=related+.

[url_Coventry_University_Podcasts-36] "Cycling is dying through drugs" (video). Blog Archive. Coventry University Podcasts. 2009-06-12. http://coventryuniversity.podbean.com/2009/06/12/greg-lemond-cycling-is-dying-through-drugs/+.

[urld3epuodzu3wuis.cloudfront.net-37] "Emma OReilly Affidavit" (pdf). U.S. Postal Service Pro Cycling Team Investigation. USADA. 2012-10-09. http://d3epuodzu3wuis.cloudfront.net/OReilly%2c+Emma+Affidavit.pdf.

[urlwww.velonation.com-38] Andrews C (2010-07-28). "Greg LeMond's suggestions for a credible future for cycling". VeloNation LLC. http://www.velonation.com/News/ID/5050/Greg-LeMonds-suggestions-for-a-credible-future-for-cycling.aspx.

[39] Ahmet Höke (2005). Erythropoietin and the Nervous System. Berlin: Springer. ISBN 0-387-30010-4. OCLC 64571745. http://books.google.com/?id=A76u7g0QnskC.

[pmid18467-40] Miyake T; Kung, CK; Goldwasser, E (Aug 1997). "Purification of human erythropoietin". J. Biol. Chem. 252 (15): 5558–5564. PMID 18467. http://www.jbc.org/content/252/15/5558.long.

[isbn0-375-76094-6-41] Angell, Marcia (2005). The Truth About the Drug Companies : How They Deceive Us and What to Do About It. New York: Random House Trade Paperbacks. p. 60. ISBN 0-375-76094-6.

[pmid3537801-42] Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". N. Engl. J. Med. 316 (2): 73–8. doi:10.1056/NEJM198701083160203. PMID 3537801.

[pmid3865178-43] Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (November 1985). "Cloning and expression of the human erythropoietin gene". Proc. Natl. Acad. Sci. U.S.A. 82 (22): 7580–4. doi:10.1073/pnas.82.22.7580. PMC 391376. PMID 3865178. http://www.pnas.org/content/82/22/7580.abstract.

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