Thrombopoietin

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Thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor)
PDB rendering based on 1v7m.
Available structures: 1v7m, 1v7n
Identifiers
Symbol(s) THPO; MGC163194; MGDF; MKCSF; ML; MPLLG; TPO
External IDs OMIM: 600044 MGI: 101875 Homologene: 398
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 7066 21832
Ensembl ENSG00000090534 ENSMUSG00000022847
Uniprot P40225 Q543R9
Refseq NM_199228 (mRNA)
NP_954698 (protein)		 NM_009379 (mRNA)
NP_033405 (protein)
Location Chr 3: 185.57 - 185.58 Mb Chr 16: 20.64 - 20.64 Mb
Pubmed search [1] [2]

Thrombopoietin leukemia virus oncogene ligand, megakaryocyte growth and development factor), also known as THPO, is a glycoprotein hormone produced mainly by the liver and the kidney that regulates the production of platelets by the bone marrow. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets.[1]


Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.[2]


Contents

The thrombopoietin gene is located on the long arm of chromosome 3 (q26.3-27). Abnormalities in this gene occur in some hereditary forms of thrombocytosis (high platelet count) and in some cases of leukemia. Thrombopoietin shares its first 153 amino acids with erythropoietin.[3]

In the liver it is produced by parenchymal cells and sinusoidal endothelial cells. In the kidney it is made by proximal convoluted tubule cells. Along with these it is made by striated muscle and stromal cells in the bone marrow.[1] In the liver, its production is augmented by interleukin 6 (IL-6).[1]

Thrombopoietin regulates the differentiation of megakaryocytes and platelets, but studies on the removal of the thrombopoeitin receptor show that its effects on hematopoiesis are more versatile[1].

Its negative feedback is different from most hormones in endocrinology: the effector regulates the hormone directly. Thrombopoeitin is bound to the surface of platelets by the mpl receptor (CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone.[1]

Despite numerous trials, thrombopoeitin is not used therapeutically. Theoretical uses include the procurement of platelets for donation[4], recovery of platelet counts after myelosuppressive chemotherapy.[1]

A modified recombinant form, termed "megakaryocyte growth and differentiation factor" (MGDF), caused a paradoxical reaction, delaying the development of therapeutic thrombopoietin. A quadrivalent peptide analogue is undergoing development, as well as several small molecule agents,[1] including several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.[5][6]

Thrombopoietin was cloned by five independent groups in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to the cell surface receptor c-Mpl, and in older publications thrombopoietin is described as c-Mpl ligand (the agent that binds to the c-Mpl molecule). Thrombopoietin is one of the Class I hematopoietic cytokines.[1]

  1. ^ a b c d e f g h Kaushansky K (2006). "Lineage-specific hematopoietic growth factors". N. Engl. J. Med. 354 (19): 2034–45. doi:10.1056/NEJMra052706. PMID 16687716. 
  2. ^ Entrez Gene: THPO thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor).
  3. ^ Online 'Mendelian Inheritance in Man' (OMIM) 600044
  4. ^ Kuter DJ, Goodnough LT, Romo J, et al (2001). "Thrombopoietin therapy increases platelet yields in healthy platelet donors". Blood 98 (5): 1339–45. PMID 11520780. 
  5. ^ Nakamura T, Miyakawa Y, Miyamura A, et al (2006). "A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis". Blood 107 (11): 4300–7. doi:10.1182/blood-2005-11-4433. PMID 16484588. 
  6. ^ Jenkins JM, Williams D, Deng Y, et al (2007). "Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist". Blood 109 (11): 4739–41. doi:10.1182/blood-2006-11-057968. PMID 17327409. 

  • Kato T, Matsumoto A, Ogami K, et al. (1999). "Native thrombopoietin: structure and function.". Stem Cells 16 (5): 322-8. PMID 9766811. 
  • Kato T (2000). "Protein characteristics of thrombopoietin.". Stem Cells 14 Suppl 1: 139-47. PMID 11012214. 
  • Geddis AE, Linden HM, Kaushansky K (2002). "Thrombopoietin: a pan-hematopoietic cytokine.". Cytokine Growth Factor Rev. 13 (1): 61-73. PMID 11750880. 
  • von dem Borne A, Folman C, van den Oudenrijn S, et al. (2002). "The potential role of thrombopoietin in idiopathic thrombocytopenic purpura.". Blood Rev. 16 (1): 57-9. doi:10.1054/blre.2001.0184. PMID 11913997. 
  • Kaushansky K (2003). "Thrombopoietin: from theory to reality.". Int. J. Hematol. 76 Suppl 1: 343-5. PMID 12430879. 
  • Kralovics R, Skoda RC (2005). "Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders.". Blood Rev. 19 (1): 1-13. doi:10.1016/j.blre.2004.02.002. PMID 15572213. 
  • Migliaccio AR, Rana RA, Vannucchi AM, Manzoli FA (2007). "Role of thrombopoietin in mast cell differentiation.". Ann. N. Y. Acad. Sci. 1106: 152-74. doi:10.1196/annals.1392.024. PMID 17468237. 
  • Foster DC, Sprecher CA, Grant FJ, et al. (1995). "Human thrombopoietin: gene structure, cDNA sequence, expression, and chromosomal localization.". Proc. Natl. Acad. Sci. U.S.A. 91 (26): 13023-7. PMID 7809166. 
  • Chang MS, McNinch J, Basu R, et al. (1995). "Cloning and characterization of the human megakaryocyte growth and development factor (MGDF) gene.". J. Biol. Chem. 270 (2): 511-4. PMID 7822271. 
  • Gurney AL, Kuang WJ, Xie MH, et al. (1995). "Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin.". Blood 85 (4): 981-8. PMID 7849319. 
  • Sohma Y, Akahori H, Seki N, et al. (1994). "Molecular cloning and chromosomal localization of the human thrombopoietin gene.". FEBS Lett. 353 (1): 57-61. PMID 7926023. 
  • Bartley TD, Bogenberger J, Hunt P, et al. (1994). "Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl.". Cell 77 (7): 1117-24. PMID 8020099. 
  • de Sauvage FJ, Hass PE, Spencer SD, et al. (1994). "Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand.". Nature 369 (6481): 533-8. doi:10.1038/369533a0. PMID 8202154. 
  • Kaushansky K, Lok S, Holly RD, et al. (1994). "Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin.". Nature 369 (6481): 568-71. doi:10.1038/369568a0. PMID 8202159. 
  • Wendling F, Maraskovsky E, Debili N, et al. (1994). "cMpl ligand is a humoral regulator of megakaryocytopoiesis.". Nature 369 (6481): 571-4. doi:10.1038/369571a0. PMID 8202160. 
  • Kato T, Ogami K, Shimada Y, et al. (1996). "Purification and characterization of thrombopoietin.". J. Biochem. 118 (1): 229-36. PMID 8537317. 
  • Hoffman RC, Andersen H, Walker K, et al. (1997). "Peptide, disulfide, and glycosylation mapping of recombinant human thrombopoietin from ser1 to Arg246.". Biochemistry 35 (47): 14849-61. doi:10.1021/bi961075b. PMID 8942648. 
  • Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC (1998). "An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia.". Nat. Genet. 18 (1): 49-52. doi:10.1038/ng0198-49. PMID 9425899. 
  • Kondo T, Okabe M, Sanada M, et al. (1998). "Familial essential thrombocythemia associated with one-base deletion in the 5'-untranslated region of the thrombopoietin gene.". Blood 92 (4): 1091-6. PMID 9694695. 

  1. ^ a b c d e f g h Kaushansky K (2006). "Lineage-specific hematopoietic growth factors". N. Engl. J. Med. 354 (19): 2034–45. doi:10.1056/NEJMra052706. PMID 16687716. 
  2. ^ Entrez Gene: THPO thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor).
  3. ^ Online 'Mendelian Inheritance in Man' (OMIM) 600044
  4. ^ Kuter DJ, Goodnough LT, Romo J, et al (2001). "Thrombopoietin therapy increases platelet yields in healthy platelet donors". Blood 98 (5): 1339–45. PMID 11520780. 
  5. ^ Nakamura T, Miyakawa Y, Miyamura A, et al (2006). "A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis". Blood 107 (11): 4300–7. doi:10.1182/blood-2005-11-4433. PMID 16484588. 
  6. ^ Jenkins JM, Williams D, Deng Y, et al (2007). "Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist". Blood 109 (11): 4739–41. doi:10.1182/blood-2006-11-057968. PMID 17327409. 

v • d • e
Cytokines, glycoproteins: colony-stimulating factors
Numbered Macrophage colony-stimulating factor - Granulocyte macrophage colony-stimulating factor - Granulocyte colony-stimulating factor
Unnumbered Erythropoietin - Thrombopoietin - Interleukin 3
v • d • e
Protein: glycoproteins
Activin - ADAM protein - Alpha 1-antichymotrypsin - Apolipoprotein H - CD70 - Asialoglycoprotein - Avidin - B-cell activating factor - 4-1BB ligand - Cholesterylester transfer protein - Clusterin - Colony-stimulating factor - Haemopexin - Inhibin - Lactoferrin - Membrane glycoproteins - Mucoprotein - Myelin protein zero - Osteonectin - Protein C - Protein S - Proteoglycan - Serum Amyloid P component - Sialoglycoprotein (CD43, Glycophorin, Glycophorin C) - Thrombopoietin - Thyroglobulin - Thyroxine-binding proteins - Transcortin - Tumor necrosis factor-alpha - Uteroglobin - Vitronectin
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