Thrombopoietin

Last updated
THPO
Protein THPO PDB 1v7m.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases THPO , MGDF, MKCSF, ML, MPLLG, THCYT1, TPO, thrombopoietin
External IDs OMIM: 600044 MGI: 101875 HomoloGene: 398 GeneCards: THPO
Gene location (Human)
Ideogram human chromosome 3.svg
Chr. Chromosome 3 (human) [1]
Human chromosome 3 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 3q27.1Start184,371,935 bp [1]
End184,381,968 bp [1]
RNA expression pattern
PBB GE THPO 211155 s at fs.png

PBB GE THPO 211831 s at fs.png

PBB GE THPO 211154 at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001173505
NM_009379
NM_001289894
NM_001289896

RefSeq (protein)

NP_001166976
NP_001276823
NP_001276825
NP_033405

Location (UCSC) Chr 3: 184.37 – 184.38 Mb Chr 16: 20.72 – 20.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the THPO gene.

Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the production of platelets. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that bud off large numbers of platelets. [5]

Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor 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. [6]

Genetics

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. The first 155 amino acids of the protein share homology with erythropoietin. [7]

Function and regulation

Thrombopoietin is produced in the liver by both parenchymal cells and sinusoidal endothelial cells, as well as in the kidney by proximal convoluted tubule cells. Small amounts are also made by striated muscle and bone marrow stromal cells. [5] In the liver, its production is augmented by interleukin 6 (IL-6). [5] However, the liver and the kidney are the primary sites of thrombopoietin production.

Thrombopoietin regulates the differentiation of megakaryocytes and platelets, but studies on the removal of the thrombopoietin receptor show that its effects on hematopoiesis are more versatile. [5]

Its negative feedback is different from that of most hormones in endocrinology: The effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets and megakaryocytes by the mpl receptor (CD 110). Inside the platelets it gets destroyed, while inside the megakaryocytes it gives the signal of their maturation and consecutively more platelet production. The bounding of the hormone at these cells thereby reduces further megakaryocyte exposure to the hormone. [5] Therefore, the rising and dropping platelet and megakaryocyte concentrations regulate the thrombopoietin levels. Low platelets and megakaryocytes lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells, leading to differentiation into megakaryocytes and further maturation of these cells. On the other hand, high platelet and megakaryocyte concentrations lead to more thrombopoetin destruction and thus less availability of thrombopoietin to bone marrow.

TPO, like EPO, plays a role in brain development. It promotes apoptosis of newly generated neurons, an effect counteracted by EPO and neurotrophins. [8]

Therapeutic use

Despite numerous trials, thrombopoietin has not been found to be useful therapeutically. Theoretical uses include the procurement of platelets for donation, [9] and recovery of platelet counts after myelosuppressive chemotherapy. [5]

Trials of a modified recombinant form, megakaryocyte growth and differentiation factor (MGDF), were stopped when healthy volunteers developed autoantibodies to endogenous thrombopoietin and then developed thrombocytopenia. [10] Romiplostim and Eltrombopag, structurally different compounds that stimulate the same pathway, are used instead. [11]

A quadrivalent peptide analogue is being investigated, as well as several small-molecule agents, [5] and several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues. [12] [13]

Discovery

Thrombopoietin was cloned by five independent teams 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. [5]

See also

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

Platelet component of blood aiding in coagulation.

Platelets, also called thrombocytes, are a component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus: they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow, which then enter the circulation. Circulating unactivated platelets are biconvex discoid (lens-shaped) structures, 2–3 µm in greatest diameter. Activated platelets have cell membrane projections covering their surface. Platelets are found only in mammals, whereas in other vertebrates thrombocytes circulate as intact mononuclear cells.

Immune thrombocytopenic purpura primary thrombocytopenia that involves relatively few platelets in blood as a result of autoantibodies

Immune thrombocytopenia purpura (ITP), also known as idiopathic thrombocytopenic purpura, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of other causes of low platelets. It causes a characteristic red or purple bruise-like rash and an increased tendency to bleed. Two distinct clinical syndromes manifest as an acute condition in children and a chronic condition in adults. The acute form often follows an infection and spontaneously resolves within two months. Chronic immune thrombocytopenia persists longer than six months with a specific cause being unknown.

Megakaryocyte large bone marrow cell responsible for the production of platelets

A megakaryocyte is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.

Wiskott–Aldrich syndrome rare disease

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present similar but less severe symptoms and are caused by mutations of the same gene.

Primary myelofibrosis is a relatively rare bone marrow/blood cancer. It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.

GATA1 protein-coding gene in the species Homo sapiens

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

Stem cell factor mammalian protein found in Homo sapiens

Stem cell factor is a cytokine that binds to the c-KIT receptor (CD117). SCF can exist both as a transmembrane protein and a soluble protein. This cytokine plays an important role in hematopoiesis, spermatogenesis, and melanogenesis.

PDGFRB protein-coding gene in the species Homo sapiens

Platelet-derived growth factor receptor beta is a protein that in humans is encoded by the PDGFRB gene.

P2RX1 protein-coding gene in the species Homo sapiens

P2X purinoceptor 1 is a protein that in humans is encoded by the P2RX1 gene.

FLT3LG protein-coding gene in the species Homo sapiens

Fms-related tyrosine kinase 3 ligand (FLT3LG) is a protein which in humans is encoded by the FLT3LG gene.

Eltrombopag chemical compound

Eltrombopag is a medication that has been developed for certain conditions that lead to thrombocytopenia. It is a small molecule agonist of the c-mpl (TpoR) receptor, which is the physiological target of the hormone thrombopoietin. Eltrombopag was discovered as a result of research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals. Designated an orphan drug in the United States and European Union, it is being manufactured and marketed by Novartis under the trade name Promacta in the US and is marketed as Revolade in the EU. Novartis acquired the drug as a part of its asset swap deal with GlaxoSmithKline.

The Harrington–Hollingsworth experiment was an experiment that established the autoimmune nature of the blood disorder immune thrombocytopenic purpura. It was performed in 1950 by the academic staff of Barnes-Jewish Hospital in St. Louis, Missouri.

Thrombopoietin receptor protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

SH2B3 protein-coding gene in the species Homo sapiens

SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3 gene on chromosome 12.

Romiplostim pharmaceutical drug

Romiplostim is a fusion protein analog of thrombopoietin, a hormone that regulates platelet production.

Congenital amegakaryocytic thrombocytopenia thrombocytopenia characterized by a severe reduction in megakaryocyte and platelet numbers that has material basis in homozygous or compound heterozygous mutation in the MPL gene on chromosome 1p34

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder.

Thrombopoiesis is the process of thrombocyte generation. Thromobocytes are ligations of the cytoplasm from megakaryocytes. A single megakaryocyte can give rise to thousands of thrombocytes.

Kenneth Kaushansky, M.D., Master of the American College of Physicians (MACP) is an American medical doctor, hematologist, former editor of the medical journal Blood, and has served as the Dean of the Stony Brook University School of Medicine since July 2010. Prior to moving to Stony Brook, he was the Helen M. Ranney Professor, and Chair of the Department of Medicine at University of California, San Diego School of Medicine.

William Vainchenker French physician

William Vainchenker, born on 16 December 1947, is a French medical doctor and researcher. He is considered a specialist in hematopoiesis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000090534 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022847 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 7 8 Kaushansky K (May 2006). "Lineage-specific hematopoietic growth factors". The New England Journal of Medicine. 354 (19): 2034–45. doi:10.1056/NEJMra052706. PMID   16687716.
  6. "Entrez Gene: THPO thrombopoietin (myeloproliferative leukemia virus oncogene ligand, megakaryocyte growth and development factor)".
  7. Online Mendelian Inheritance in Man (OMIM) 600044
  8. Ehrenreich H, Hasselblatt M, Knerlich F, von Ahsen N, Jacob S, Sperling S, et al. (January 2005). "A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain". Proceedings of the National Academy of Sciences of the United States of America. 102 (3): 862–7. doi: 10.1073/pnas.0406008102 . PMC   545528 . PMID   15642952.
  9. Kuter DJ, Goodnough LT, Romo J, DiPersio J, Peterson R, Tomita D, et al. (September 2001). "Thrombopoietin therapy increases platelet yields in healthy platelet donors". Blood. 98 (5): 1339–45. doi:10.1182/blood.V98.5.1339. PMID   11520780.
  10. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ (December 2001). "Thrombocytopenia caused by the development of antibodies to thrombopoietin". Blood. 98 (12): 3241–8. doi: 10.1182/blood.V98.12.3241 . PMID   11719360.
  11. Imbach P, Crowther M (August 2011). "Thrombopoietin-receptor agonists for primary immune thrombocytopenia". The New England Journal of Medicine. 365 (8): 734–41. doi:10.1056/NEJMct1014202. PMID   21864167.
  12. Nakamura T, Miyakawa Y, Miyamura A, Yamane A, Suzuki H, Ito M, et al. (June 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.
  13. Jenkins JM, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, Erickson-Miller CL (June 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.

Further reading