Summary: Granulocyte-macrophage colony-stimulating factor
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This is the Wikipedia entry entitled "Granulocyte macrophage colony-stimulating factor". More...
Granulocyte macrophage colony-stimulating factor Edit Wikipedia article
| Granulocyte-macrophage colony-stimulating factor | |||||||||
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| three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor | |||||||||
| Identifiers | |||||||||
| Symbol | GM_CSF | ||||||||
| Pfam | PF01109 | ||||||||
| Pfam clan | CL0053 | ||||||||
| InterPro | IPR000773 | ||||||||
| PROSITE | PDOC00584 | ||||||||
| SCOP | 2gmf | ||||||||
| SUPERFAMILY | 2gmf | ||||||||
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| Systematic (IUPAC) name | |
|---|---|
| Human granulocyte macrophage colony stimulating factor | |
| Clinical data | |
| Pregnancy cat. | ? |
| Legal status | ? |
| Identifiers | |
| CAS number | 83869-56-1 |
| ATC code | L03AA09 |
| DrugBank | DB00020 |
| Chemical data | |
| Formula | C639H1006N168O196S8 |
| Mol. mass | 14434.5 g/mol |
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a protein secreted by macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts.
Contents |
[edit] Functions
GM-CSF is a cytokine that functions as a white blood cell growth factor. GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can rapidly lead to an increase in their numbers, a process crucial for fighting infection. The active form of the protein is found extracellularly as a homodimer.
[edit] Genetics
The human gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Genes in the cluster include those encoding interleukins 4, 5, and 13.[1]
[edit] Glycosylation
Human granulocyte macrophage colony-stimulating factor is glycosylated in its mature form.
[edit] Clinical significance
GM-CSF is also known as molgramostim or, when the protein is expressed in yeast cells, sargramostim (Leukine).
GM-CSF is used as a medication to stimulate the production of white blood cells following chemotherapy.
GM-CSF has also recently been evaluated in clinical trials for its potential as a vaccine adjuvant in HIV-infected patients. The preliminary results have been promising[2] but GM-CSF is not presently FDA-approved for this purpose.
[edit] Leukine
Leukine is the trade name of sargramostim, recombinant yeast-derived GM-CSF developed at Immunex (now Amgen) and first given to six humans in 1987 as part of a compassionate-use protocol for the victims of the Goiânia cesium irradiation accident.[3] It is currently manufactured by Berlex Laboratories, a subsidiary of Schering AG. Its use was approved by U.S. Food and Drug Administration for acceleration of white blood cell recovery following autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma, acute lymphocytic leukemia, or Hodgkin's disease in March 1991.[4] In November 1996, the FDA also approved sargramostim for treatment of fungal infections and replenishment of white blood cells following chemotherapy.[5]
[edit] Controversy
Berlex funded a study that ran in the May 26, 2005 issue of the New England Journal of Medicine, which concluded that GM-CSF did produce significantly more remissions in Crohn's disease than those having received a placebo in the study, and it also decreased disease severity and improved quality of life.[6]
The study's lead author, Joshua Korzenik of Harvard Medical School and Massachusetts General Hospital, is a paid consultant for Berlex, and co-inventor of the patent, which is owned by Washington University - St. Louis.[7]
[edit] Rheumatoid arthritis
GM-CSF is found in high levels in joints with rheumatoid arthritis and blocking GM-CSF may reduce the inflammation or damage. Some drugs (e.g. MOR103) are being developed to block GM-CSF.[8]
[edit] See also
[edit] References
- ^ "Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1437.
- ^ Breitbach CJ, et al. (2011). "Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans". Nature 477 (7362): 99â102. doi:10.1038/nature10358. PMID 21886163.
- ^ By HAROLD M. SCHMECK JrPublished: November 02, 1987 (1987-11-02). "Radiation Team Sent to Brazil Saves Two With a New Drug - New York Times". Nytimes.com. http://www.nytimes.com/1987/11/02/world/radiation-team-sent-to-brazil-saves-two-with-a-new-drug.html. Retrieved 2012-06-20.
- ^ "Approval Summary for sargramostim". Oncology Tools. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 5 March 1991. Archived from the original on 29 September 2007. http://web.archive.org/web/20070624223312/www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=353. Retrieved 20 September 2009.
- ^ "Newly Approved Drug Therapies (179): Leukine (sargramostim), Immunex". CenterWatch. http://www.centerwatch.com/patient/drugs/dru179.html. Retrieved 12 October 2008.
- ^ Korzenik J, Dieckgraefe B, Valentine J, Hausman D, Gilbert M (2005). "Sargramostim for active Crohn's disease". N Engl J Med 352 (21): 2193â201. doi:10.1056/NEJMoa041109. PMID 15917384.
- ^ Bernstein DS (2006-04-12). "Med school drug pushers: How scientists are selling out to drug companies". The Boston Phoenix. http://www.thephoenix.com/Article.aspx?id=8920&page=1. Retrieved 2008-10-12.
- ^ "MOR103 - Antibody for the Treatment of Rheumatoid Arthritis, Germany". 2010. http://www.drugdevelopment-technology.com/projects/mor103/.
[edit] Further reading
- Esnault S, Malter JS (2002). "GM-CSF regulation in eosinophils". Arch. Immunol. Ther. Exp. (Warsz.) 50 (2): 121â30. PMID 12022701.
- Martinez-Moczygemba M, Huston DP (2003). "Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF". J. Allergy Clin. Immunol. 112 (4): 653â65; quiz 666. doi:10.1016/j.jaci.2003.08.015. PMID 14564341.
- Mroczko B, Szmitkowski M (2005). "Hematopoietic cytokines as tumor markers". Clin. Chem. Lab. Med. 42 (12): 1347â54. doi:10.1515/CCLM.2004.253. PMID 15576295.
- Hamilton JA, Anderson GP (2005). "GM-CSF Biology". Growth Factors 22 (4): 225â31. doi:10.1080/08977190412331279881. PMID 15621725.
- Tortorella C, Simone O, Piazzolla G et al. (2007). "Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins". Ageing Res. Rev. 6 (2): 81â93. doi:10.1016/j.arr.2006.10.001. PMID 17142110.
- Robertson SA (2007). "GM-CSF regulation of embryo development and pregnancy". Cytokine Growth Factor Rev. 18 (3â4): 287â98. doi:10.1016/j.cytogfr.2007.04.008. PMID 17512774.
- Morales JK, Kmieciak M, Knutson KL, Bear HD, Manjili MH (2009). "GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11bâGr1â bone marrow progenitor cells into myeloid-derived suppressor cells". Breast Cancer Res Treat. 123 (1): 39â49. doi:10.1007/s10549-009-0622-8. PMC 3095485. PMID 19898981. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3095485/.
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[edit] External links
- Official gentaur web site
- Official Leukine web site
- Granulocyte-Macrophage Colony-Stimulating Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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External database links
| PANDIT: | PF01109 |
| PROSITE: | PDOC00584 |
| Pseudofam: | PF01109 |
| SCOP: | 2gmf |
| SYSTERS: | GM_CSF |
This tab holds annotation information from the InterPro database.
InterPro entry IPR000773
Granulocyte-macrophage colony-stimulating factor (GMCSF) is a cytokine that acts in hematopoiesis to stimulate growth and differentiation of hematopoietic precursor cells from various lineages including granulocytes, macrophages, eosinophils and erythrocytes [PUBMED:2458827, PUBMED:1569568]. GMCSF is a glycoprotein of ~120 residues that contains 4 conserved cysteines that participate in disulphide bond formation. The crystal structure of recombinant human GMCSF has been determined [PUBMED:1569568]. There are two molecules in the asymmetric unit, which are related by an approximate non-crystallographic 2-fold axis. The overall structure, which is highly compact and globular with a predominantly hydrophobic core, is characterised by a 4-alpha-helix bundle. The helices are arranged in a left-handed anti-parallel fashion, with two overhand connections. Within the connections is a two-stranded anti-parallel beta-sheet. The tertiary structure has a topology similar to that of Sus scrofa (pig) growth factor and interferon-beta. Most of the proposed critical regions for receptor binding are located on a continuous surface at one end of the molecule that includes the C terminus [PUBMED:1569568].Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Cellular component | extracellular region (GO:0005576) |
| Molecular function | growth factor activity (GO:0008083) |
| granulocyte macrophage colony-stimulating factor receptor binding (GO:0005129) | |
| Biological process | immune response (GO:0006955) |
Domain organisation
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Pfam Clan
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| Seed (7) |
Full (64) |
Representative proteomes | NCBI (68) |
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RP55 (2) |
RP75 (16) |
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| PP/heatmap | 1 | |||||||
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| Seed (7) |
Full (64) |
Representative proteomes | NCBI (68) |
Meta (0) |
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|---|---|---|---|---|---|---|---|---|
| RP15 (1) |
RP35 (1) |
RP55 (2) |
RP75 (16) |
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| Raw Stockholm | ||||||||
| Gzipped | ||||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
External links
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Sarah Teichmann |
| Previous IDs: | none |
| Type: | Domain |
| Author: | Bateman A |
| Number in seed: | 7 |
| Number in full: | 64 |
| Average length of the domain: | 118.90 aa |
| Average identity of full alignment: | 55 % |
| Average coverage of the sequence by the domain: | 84.06 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 122 | ||||||||||||
| Family (HMM) version: | 12 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Interactions
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GM_CSFStructures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GM_CSF domain has been found. There are 5 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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Archea
Eukaryota
Bacteria
Other sequences
Viruses
Unclassified
Viroids
Unclassified sequence