Granulocyte colony-stimulating factor

Colony stimulating factor 3 (granulocyte)
Crystal structure of 3 molecules of human G-CSF. From PDB 1rhg
Available structures
1cd9, 1gnc, 1pgr, 1rhg, 2d9q
Identifiers
Symbols	CSF3; G-CSF; GCSF; MGC45931
External IDs	OMIM: 138970 MGI: 1339751 HomoloGene: 7677
Gene ontology Molecular function • cytokine activity • granulocyte colony-stimulating factor receptor binding • interleukin-6 receptor binding • enzyme binding Cellular component • extracellular region • extracellular space Biological process • acute-phase response • immune response • cellular defense response • cell-cell signaling • multicellular organismal development • positive regulation of cell proliferation • cytokine and chemokine mediated signaling pathway • granulocyte differentiation
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1440	12985
Ensembl	ENSG00000108342	ENSMUSG00000038067
UniProt	P09919	Q0VB73
RefSeq	NM_000759 (mRNA)	NM_009971 (mRNA)
	NP_000750 (protein)	NP_034101 (protein)
Location	Chr 17: 35.43 - 35.43 Mb	Chr 11: 98.52 - 98.52 Mb
PubMed search	[1]	[2]

Granulocyte colony-stimulating factor (G-CSF or GCSF) is a colony-stimulating factor hormone. It is a glycoprotein, growth factor or 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. It also stimulates the survival, proliferation, differentiation, and function of neutrophil precursors and mature neutrophils. G-CSF regulate them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras /mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway. G-CSF is also known as colony-stimulating factor 3 (CSF 3).

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 proprieties 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 available in non regulated and semi-regulated countries.

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

• PEGylation

References

Further reading

v • d • e PDB Gallery 1cd9: 2:2 COMPLEX OF G-CSF WITH ITS RECEPTOR   1gnc: STRUCTURE AND DYNAMICS OF THE HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR DETERMINED BY NMR SPECTROSCOPY. LOOP MOBILITY IN A FOUR-HELIX-BUNDLE PROTEIN   1pgr: 2:2 COMPLEX OF G-CSF WITH ITS RECEPTOR   1rhg: THE STRUCTURE OF GRANULOCYTE-COLONY-STIMULATING FACTOR AND ITS RELATIONSHIP TO THOSE OF OTHER GROWTH FACTORS   2d9q: Crystal Structure of the Human GCSF-Receptor Signaling Complex

External links

• MeSH Granulocyte+Colony-Stimulating+Factor
• GCSF at The GDB Human Genome Database