Granulocyte colony-stimulating factor


Granulocyte colony-stimulating factor
Colony stimulating factor 3 (granulocyte)

Crystal structure of 3 molecules of human G-CSF. From PDB 1rhg
Identifiers
Symbols CSF3; C17orf33; CSF3OS; GCSF; MGC45931
External IDs OMIM138970 MGI1339751 HomoloGene7677 GeneCards: CSF3 Gene
RNA expression pattern
PBB GE CSF3 207442 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1440 12985
Ensembl ENSG00000108342 ENSMUSG00000038067
UniProt P09919 Q0VB73
RefSeq (mRNA) NM_000759.3 NM_009971.1
RefSeq (protein) NP_000750.1 NP_034101.1
Location (UCSC) Chr 17:
38.17 – 38.17 Mb
Chr 11:
98.56 – 98.56 Mb
PubMed search [1] [2]

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.

Contents

Discovery

Mouse granulocyte colony-stimulating factor (G-CSF) was first recognised and purified in Walter and Eliza Hall Institute, Australia in 1983,[1] and the human form was cloned by groups from Japan and the Germany/United States in 1986.[2][3]

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.[4]

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.[5][6] These properties are currently under investigations for the development of treatments of neurological diseases such as cerebral ischemia.

Genetics

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.[2]

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 prone 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. It may also be given to the receiver, to compensate for conditioning regimens.

Itescu planned in 2004 to use G-CSF to treat heart degeneration by injecting it into the blood-stream, plus SDF (stromal cell-derived factor) directly to the heart.[7]

A Washington University School of Medicine study in mice has shown that G-CSF may decrease bone mineral density.[8]

Thanks to its neuroprotective proprieties, G-CSF is currently under investigation for cerebral ischemia in a clinical phase IIb [9] and several clinical pilot studies are published for other neurological disease such as amyotrophic lateral sclerosis.[10]

Sweet's syndrome is a known side effect of using this drug.[11]

It was first marketed by Amgen with the brand name Neupogen. Several bio-generic versions are now also available in markets such as Europe and Australia.

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

References

  1. ^ Metcalf D (July 1985). "The granulocyte-macrophage colony-stimulating factors". Science 229 (4708): 16–22. doi:10.1126/science.2990035. PMID 2990035. 
  2. ^ a b 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1172228. 
  6. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2639207. 
  7. ^ Finkel, Elizabeth (2005). Stem cells: controversy on the frontiers of science. Crows Nest: ABC Books. ISBN 0-7333-1248-9. 
  8. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1852257. 
  9. ^ http://clinicaltrials.gov/ct/show/NCT00927836
  10. ^ 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.
  11. ^ 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. 

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

External links


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