Granulocyte colony-stimulating factor
|Colony stimulating factor 3 (granulocyte)|
Ribbon diagram showing three molecules of human G-CSF. From PDB 1rhg
|RNA expression pattern|
Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 (CSF 3).
It is a glycoprotein, growth factor and cytokine produced by a number of different tissues to stimulate the bone marrow to produce granulocytes and stem cells. G-CSF then stimulates the bone marrow to release them into the blood.
G-CSF also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras /mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway.
Mouse granulocyte colony-stimulating factor (G-CSF) was first recognised and purified in Walter and Eliza Hall Institute, Australia in 1983, and the human form was cloned by groups from Japan and the Germany/United States in 1986.
Biological function 
G-CSF is produced by endothelium, macrophages, and a number of other immune cells. The natural human glycoprotein exists in two forms, a 174- and 180-amino-acid-long protein of molecular weight 19,600 grams per mole. The more-abundant and more-active 174-amino acid form has been used in the development of pharmaceutical products by recombinant DNA (rDNA) technology.
The G-CSF-receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates proliferation and differentiation into mature granulocytes. G-CSF is also a potent inducer of HSCs mobilization from the bone marrow into the bloodstream, although it has been shown that it does not directly affect the hematopoietic progenitors that are mobilized.
Beside the effect on the hematopoietic system, G-CSF can also act on neuronal cells as a neurotrophic factor. Indeed, its receptor is expressed by neurons in the brain and spinal cord. The action of G-CSF in the central nervous system is to induce neurogenesis, to increase the neuroplasticity and to counteract apoptosis. These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.
The gene for G-CSF is located on chromosome 17, locus q11.2-q12. Nagata et al. found that the GCSF gene has 4 introns, and that 2 different polypeptides are synthesized from the same gene by differential splicing of mRNA.
The 2 polypeptides differ by the presence or absence of 3 amino acids. Expression studies indicate that both have authentic GCSF activity.
It is thought that stability of the G-CSF mRNA is regulated by an RNA element called the G-CSF factor stem-loop destabilising element.
Therapeutic use 
G-CSF stimulates the production of white blood cells (WBC). In oncology and hematology, a recombinant form of G-CSF is used with certain cancer patients to accelerate recovery from neutropenia after chemotherapy, allowing higher-intensity treatment regimens. Chemotherapy can cause myelosuppression and unacceptably low levels of white blood cells, making patients susceptible to infections and sepsis.
G-CSF is also used to increase the number of hematopoietic stem cells in the blood of the donor before collection by leukapheresis for use in hematopoietic stem cell transplantation. For this purpose, G-CSF appears to be safe in pregnancy during implantation as well as during the second and third trimesters. Breastfeeding should be withheld for 3 days after CSF administration to allow for clearance of it from the milk.
G-CSF may also be given to the receiver in hematopoietic stem cell transplantation, to compensate for conditioning regimens.
Due to its neuroprotective properties, G-CSF is currently under investigation for cerebral ischemia in a clinical phase IIb  and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis.
The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim. The structure of filgrastim differs slightly from the structure of the natural glycoprotein. Most published studies have used filgrastim. Filgrastim (Neupogen) and PEG-filgrastim (Neulasta) are two commercially-available forms of rhG-CSF (recombinant human G-CSF). The PEG (polyethylene glycol) form has a much longer half-life, reducing the necessity of daily injections.
Another form of recombinant human G-CSF called lenograstim is synthesised in Chinese Hamster Ovary cells (CHO cells). As this is a mammalian cell expression system, lenograstim is indistinguishable from the 174-amino acid natural human G-CSF. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies.
See also 
- Metcalf D (July 1985). "The granulocyte-macrophage colony-stimulating factors". Science 229 (4708): 16–22. doi:10.1126/science.2990035. PMID 2990035.
- Nagata S, Tsuchiya M, Asano S, Kaziro Y, Yamazaki T, Yamamoto O, Hirata Y, Kubota N, Oheda M, Nomura H (1986). "Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor". Nature 319 (6052): 415–8. doi:10.1038/319415a0. PMID 3484805.
- Souza LM, Boone TC, Gabrilove J, Lai PH, Zsebo KM, Murdock DC, Chazin VR, Bruszewski J, Lu H, Chen KK, Barendt J, Platzer, E, Moore, MAS, Mertelsmann R, Welte K (April 1986). "Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells". Science 232 (4746): 61–5. doi:10.1126/science.2420009. PMID 2420009.
- Thomas J, Liu F, Link DC (May 2002). "Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor". Curr. Opin. Hematol. 9 (3): 183–9. doi:10.1097/00062752-200205000-00002. PMID 11953662.
- Schneider A, Krüger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schäbitz WR (August 2005). "The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis". J. Clin. Invest. 115 (8): 2083–98. doi:10.1172/JCI23559. PMC 1172228. PMID 16007267.
- Pitzer C, Krüger C, Plaas C, Kirsch F, Dittgen T, Müller R, Laage R, Kastner S, Suess S, Spoelgen R, Henriques A, Ehrenreich H, Schäbitz WR, Bach A, Schneider A (December 2008). "Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis". Brain 131 (Pt 12): 3335–47. doi:10.1093/brain/awn243. PMC 2639207. PMID 18835867.
- Pessach I, Shimoni A, Nagler A (2013). "Granulocyte-colony stimulating factor for hematopoietic stem cell donation from healthy female donors during pregnancy and lactation: what do we know?". Hum. Reprod. Update 19 (3): 259–67. doi:10.1093/humupd/dms053. PMID 23287427.
- Finkel, Elizabeth (2005). Stem cells: controversy on the frontiers of science. Crows Nest: ABC Books. ISBN 0-7333-1248-9.
- Hirbe AC, Uluçkan O, Morgan EA, Eagleton MC, Prior JL, Piwnica-Worms D, Trinkaus K, Apicelli A, Weilbaecher K (April 2007). "Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner". Blood 109 (8): 3424–31. doi:10.1182/blood-2006-09-048686. PMC 1852257. PMID 17192391.
- Zang Y et al. Amyotroph Lateral Scler. 2008 Dec 4:1-2 Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis.
- Paydaş S, Sahin B, Seyrek E, Soylu M, Gonlusen G, Acar A, Tuncer I (September 1993). "Sweet's syndrome associated with G-CSF". Br. J. Haematol. 85 (1): 191–2. doi:10.1111/j.1365-2141.1993.tb08668.x. PMID 7504506.
- Weisdorf D, Chao N, Waselenko JK, et al. (June 2006). "Acute radiation injury: contingency planning for triage, supportive care, and transplantation". Biol. Blood Marrow Transplant. 12 (6): 672–82. doi:10.1016/j.bbmt.2006.02.006. PMID 16737941.
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Welte,K, et al., Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc.Natl.Acad.Sci. USA 82, 1526–1530, 1985
Metcalf D. The colony-stimulating factors and cancer. Nature Reviews Cancer 20, 425-434, 2010
Further reading 
- Duarte RF, Franf DA (2003). "The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): molecular basis and clinical relevance". Leuk. Lymphoma 43 (6): 1179–87. doi:10.1080/10428190290026231. PMID 12152985.
- Mroczko B, Szmitkowski M (2005). "Hematopoietic cytokines as tumor markers". Clin. Chem. Lab. Med. 42 (12): 1347–54. doi:10.1515/CCLM.2004.253. PMID 15576295.
- Sallerfors B, Olofsson T (1993). "Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) secretion by adherent monocytes measured by quantitative immunoassays". Eur. J. Haematol. 49 (4): 199–207. doi:10.1111/j.1600-0609.1992.tb00047.x. PMID 1281454.
- Zink T, Ross A, Ambrosius D, et al. (1993). "Secondary structure of human granulocyte colony-stimulating factor derived from NMR spectroscopy". FEBS Lett. 314 (3): 435–9. doi:10.1016/0014-5793(92)81521-M. PMID 1281794.
- Kubota N, Orita T, Hattori K, et al. (1990). "Structural characterization of natural and recombinant human granulocyte colony-stimulating factors". J. Biochem. 107 (3): 486–92. PMID 1692828.
- Nagata S, Tsuchiya M, Asano S, et al. (1986). "The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor". EMBO J. 5 (3): 575–81. PMC 1166801. PMID 2423327.
- Simmers RN, Smith J, Shannon MF, et al. (1988). "Localization of the human G-CSF gene to the region of a breakpoint in the translocation typical of acute promyelocytic leukemia". Hum. Genet. 78 (2): 134–6. doi:10.1007/BF00278182. PMID 2448221.
- Tweardy DJ, Cannizzaro LA, Palumbo AP, et al. (1988). "Molecular cloning and characterization of a cDNA for human granulocyte colony-stimulating factor (G-CSF) from a glioblastoma multiforme cell line and localization of the G-CSF gene to chromosome band 17q21". Oncogene Res. 1 (3): 209–20. PMID 2453015.
- Tsuchiya M, Nomura H, Asano S, et al. (1987). "Characterization of recombinant human granulocyte-colony-stimulating factor produced in mouse cells". EMBO J. 6 (3): 611–6. PMC 553441. PMID 3034599.
- Devlin JJ, Devlin PE, Myambo K, et al. (1987). "Expression of granulocyte colony-stimulating factor by human cell lines". J. Leukoc. Biol. 41 (4): 302–6. PMID 3494801.
- Kanda N, Fukushige S, Murotsu T, et al. (1987). "Human gene coding for granulocyte-colony stimulating factor is assigned to the q21-q22 region of chromosome 17". Somat. Cell Mol. Genet. 13 (6): 679–84. doi:10.1007/BF01534488. PMID 3499671.
- Le Beau MM, Lemons RS, Carrino JJ, et al. (1988). "Chromosomal localization of the human G-CSF gene to 17q11 proximal to the breakpoint of the t(15;17) in acute promyelocytic leukemia". Leukemia 1 (12): 795–9. PMID 3501046.
- Zink T, Ross A, Lüers K, et al. (1994). "Structure and dynamics of the human granulocyte colony-stimulating factor determined by NMR spectroscopy. Loop mobility in a four-helix-bundle protein". Biochemistry 33 (28): 8453–63. doi:10.1021/bi00194a009. PMID 7518249.
- Corcione A, Baldi L, Zupo S, et al. (1994). "Spontaneous production of granulocyte colony-stimulating factor in vitro by human B-lineage lymphocytes is a distinctive marker of germinal center cells". J. Immunol. 153 (7): 2868–77. PMID 7522243.
- Watari K, Ozawa K, Tajika K, et al. (1994). "Production of human granulocyte colony stimulating factor by various kinds of stromal cells in vitro detected by enzyme immunoassay and in situ hybridization". Stem Cells 12 (4): 416–23. doi:10.1002/stem.5530120409. PMID 7524894.
- Hill CP, Osslund TD, Eisenberg D (1993). "The structure of granulocyte-colony-stimulating factor and its relationship to other growth factors". Proc. Natl. Acad. Sci. U.S.A. 90 (11): 5167–71. doi:10.1073/pnas.90.11.5167. PMC 46676. PMID 7685117.
- Haniu M, Horan T, Arakawa T, et al. (1996). "Extracellular domain of granulocyte-colony stimulating factor receptor. Interaction with its ligand and identification of a domain in close proximity of ligand-binding region". Arch. Biochem. Biophys. 324 (2): 344–56. doi:10.1006/abbi.1995.0047. PMID 8554326.
- McCracken S, Layton JE, Shorter SC, et al. (1996). "Expression of granulocyte-colony stimulating factor and its receptor is regulated during the development of the human placenta". J. Endocrinol. 149 (2): 249–58. doi:10.1677/joe.0.1490249. PMID 8708536.
- Granulocyte Colony-Stimulating Factor at the US National Library of Medicine Medical Subject Headings (MeSH)