Summary: Granulocyte-macrophage colony-stimulating factor
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Granulocyte macrophage colony-stimulating factor Edit Wikipedia article
|, GMCSF, colony stimulating factor 2|
|RNA expression pattern|
|View/Edit Human||View/Edit Mouse|
|Granulocyte-macrophage colony-stimulating factor|
three-dimensional structure of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM_CSF)
|ATC code||L03AA09 (WHO)|
|Chemical and physical data|
|Molar mass||14434.5 g/mol|
|(what is this?)|
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.
GM-CSF is a monomeric glycoprotein that functions as a cytokine - it is 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.
GM-CSF also has some effects on mature cells of the immune system. These include, for example, inhibiting neutrophil migration and causing an alteration of the receptors expressed on the cells surface.
GM-CSF signals via signal transducer and activator of transcription, STAT5. In macrophages, it has also been shown to signal via STAT3. The cytokine activates macrophages to inhibit fungal survival. It induces deprivation in intracellular free zinc and increases production of reactive oxygen species that culminate in fungal zinc starvation and toxicity. Thus, GM-CSF facilitates development of the immune system and promotes defense against infections.
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.
Human granulocyte macrophage colony-stimulating factor is glycosylated in its mature form.
GM-CSF is manufactured using recombinant DNA technology and is marketed as a protein therapeutic called molgramostim or, when the protein is expressed in yeast cells, sargramostim. It is used as a medication to stimulate the production of white blood cells and thus prevent neutropenia following chemotherapy.
The sequence of human GM-CSF was first identified in 1985 and soon three recominbant human GM-CSFs were produced, one in bacteria, one in mammalian cells, and one in yeast; Immunex developed GM-CSF manufactured in yeast into sargramostim ( Leukine). Clinical trials of sargramostim were initiated in 1987; in that same year it was administered to six people as part of a compassionate-use protocol for the victims of cesium irradiation from the Goiânia accident.
It was approved by the FDA in March 1991 under the trade name Leukine 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 November 1996, the FDA also approved sargramostim for treatment of fungal infections and replenishment of white blood cells following chemotherapy. A liquid formulation was approved in 1995. Immunex was acquired by Amgen in 2002. As part of the acquisition, Leukine was spun off to Berlex, which became Bayer HealthCare in 2007. In 2009, Genzyme acquired the rights to Leukine from Bayer, including the manufacturing facility in the Seattle area.
- Granulocyte macrophage colony-stimulating factor receptor
- Filgrastim (Neupogen, a granulocyte colony-stimulating factor (G-CSF) analog)
- Pegfilgrastim (Neulasta, a PEGylated form filgrastim)
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Root RK, Dale DC (1999). "Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: comparisons and potential for use in the treatment of infections in nonneutropenic patients". The Journal of Infectious Diseases. 179 (Suppl 2): S342–352. PMID 10081506.
- Francisco-Cruz A, Aguilar-Santelises M, Ramos-Espinosa O, Mata-Espinosa D, Marquina-Castillo B, Barrios-Payan J, Hernandez-Pando R (Jan 2014). "Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor". Medical Oncology. 31 (1): 774. doi:10.1007/s12032-013-0774-6. PMID 24264600.
- Gasson JC (Mar 1991). "Molecular physiology of granulocyte-macrophage colony-stimulating factor". Blood. 77 (6): 1131–45. PMID 2001448.
- Voehringer D (Oct 2012). "Basophil modulation by cytokine instruction". European Journal of Immunology. 42 (10): 2544–50. doi:10.1002/eji.201142318. PMID 23042651.
- Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe GS (Oct 2013). "Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival". Immunity. 39 (4): 697–710. doi:10.1016/j.immuni.2013.09.006. PMC . PMID 24138881.
- Hansen PJ, Dobbs KB, Denicol AC (Sep 2014). "Programming of the preimplantation embryo by the embryokine colony stimulating factor 2". Animal Reproduction Science. 149 (1-2): 59–66. doi:10.1016/j.anireprosci.2014.05.017. PMID 24954585.
- "Entrez Gene: CSF2 colony stimulating factor 2 (granulocyte-macrophage)".
- Vacchelli E, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L (Jul 2013). "Trial Watch: Immunostimulatory cytokines". Oncoimmunology. 2 (7): e24850. doi:10.4161/onci.24850. PMC . PMID 24073369.
- Hellerstein M, Xu Y, Marino T, Lu S, Yi H, Wright ER, Robinson HL (Nov 2012). "Co-expression of HIV-1 virus-like particles and granulocyte-macrophage colony stimulating factor by GEO-D03 DNA vaccine". Human Vaccines & Immunotherapeutics. 8 (11): 1654–8. doi:10.4161/hv.21978. PMC . PMID 23111169.
- Iyer SS, Amara RR (2014). "DNA/MVA Vaccines for HIV/AIDS". Vaccines. 2 (1): 160–78. doi:10.3390/vaccines2010160. PMC . PMID 26344473.
- Armitage JO (December 1998). "Emerging applications of recombinant human granulocyte-macrophage colony-stimulating factor". Blood. 92 (12): 4491–508. PMID 9845514.
- Staff (May 2008). "Back to the Future: Original Liquid Leukine® Coming Soon" (PDF). Oncology Business Review.
- "Immunex Corporation". Company Histories & Profiles. FundingUniverse.com. Retrieved 12 November 2011.
- Schmeck HM (1987-11-02). "Radiation Team Sent to Brazil Saves Two With a New Drug". New York Times. Retrieved 2012-06-20.
- "Approval Summary for sargramostim". Oncology Tools. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 1991-03-05. Archived from the original on 2007-06-24. Retrieved 20 September 2009.
- "Newly Approved Drug Therapies (179): Leukine (sargramostim), Immunex". CenterWatch. Retrieved 2008-10-12.
- "Bayer Healthcare Pharmaceuticals Plant, Snohomish County, Washington State". pharmaceutical-technology.com. Retrieved 12 November 2011.
- "Genzyme and Bayer HealthCare Enter New Strategic Agreement". Genzyme. March 31, 2009. Retrieved 12 November 2011.
- Deiß A, Brecht I, Haarmann A, Buttmann M (Mar 2013). "Treating multiple sclerosis with monoclonal antibodies: a 2013 update". Expert Review of Neurotherapeutics. 13 (3): 313–35. doi:10.1586/ern.13.17. PMID 23448220.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR000773Granulocyte-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].
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)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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Cytokines are regulatory peptides that can be produced by various cells for communicating and orchestrating the large multicellular system. Cytokines are key mediators of hematopoiesis, immunity, allergy, inflammation, tissue remodeling, angiogenesis, and embryonic development . This superfamily includes both the long and short chain helical cytokines.
The clan contains the following 25 members:CNTF CSF-1 EPO_TPO Flt3_lig GCSF GM_CSF Hormone_1 IFN-gamma IL10 IL11 IL12 IL13 IL15 IL2 IL22 IL3 IL34 IL4 IL5 IL6 Interferon Leptin LIF_OSM PRF SCF
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You can see the alignments as HTML or in three different sequence viewers:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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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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|Seed source:||Sarah Teichmann|
|Number in seed:||7|
|Number in full:||43|
|Average length of the domain:||118.70 aa|
|Average identity of full alignment:||58 %|
|Average coverage of the sequence by the domain:||75.80 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||15|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 12 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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