Alternative titles; symbols
HGNC Approved Gene Symbol: CSF3
Cytogenetic location: 17q21.1 Genomic coordinates (GRCh38): 17:40,015,440-40,017,813 (from NCBI)
Granulocyte colony-stimulating factor (or colony stimulating factor-3) specifically stimulates the proliferation and differentiation of the progenitor cells for granulocytes (Metcalf, 1985). Nagata et al. (1986) determined the partial amino acid sequence of purified GCSF protein, and by using oligonucleotides as probes, isolated several GCSF cDNA clones from a human squamous carcinoma cell line cDNA library. Cloning of human GCSF cDNA shows that a single gene codes for a 177- or 180-amino acid mature protein of molecular weight 19,600 (Nagata et al., 1986; Souza et al., 1986).
Nagata et al. (1986) 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.
By somatic cell hybridization and in situ chromosomal hybridization, Le Beau et al. (1987) mapped the GCSF gene to 17q11 in the region of the breakpoint in the 15;17 translocation characteristic of acute promyelocytic leukemia. Further studies indicated that the gene is proximal to the said breakpoint and that it remains on the rearranged chromosome 17. Southern blot analysis using both conventional and pulsed field gel electrophoresis showed no rearranged restriction fragments. By use of a full-length cDNA clone as a hybridization probe in human-mouse somatic cell hybrids and in flow-sorted human chromosomes, Kanda et al. (1987) mapped the gene for GCSF to 17q21-q22. Simmers et al. (1988) mapped the GCSF gene to 17q11.2-q21 by in situ hybridization. Tweardy et al. (1987) also assigned CSF3 to 17q21 by in situ hybridization. CSF3 and CRYB1 (123610) are located on the same large restriction fragment (HGM10).
Tweardy et al. (1987) found stimulatory activity from a glioblastoma multiforme cell line that was biologically and biochemically indistinguishable from GCSF produced by a bladder cell line.
In a 60-year-old female with ovarian carcinoma and associated marked leukocytosis, Sudo et al. (1996) showed with immunohistochemical studies that the tumor cells are stained with anti-GCSF monoclonal antibody. Serum GCSF concentration was elevated, furthermore. Neutrophils predominated in the very high white cell count which at the highest was 95.3 x 10(9)/l. The patient died of respiratory failure.
Petit et al. (2002) investigated the mobilization of hematopoietic progenitor stem cells (HPCs) induced by GCSF, a method widely used in clinical transplantation. ELISA and immunohistologic analysis showed a significant reduction in SDF1 (CXCL12; 600835) in human and mouse bone marrow plasma and immature osteoblasts, but not peripheral blood, within 24 hours of GCSF treatment. They also noted that the decline is preceded by a sharp transient increase of marrow plasma SDF1 protein and osteoblast mRNA immediately after GCSF injection. Immunoblot analysis determined that the reduction of SDF1 is mediated by neutrophil elastase (130130). In vivo, chemotaxis by SDF1 was partially restored by elastase inhibition. In contrast, expression of the SDF1 receptor, CXCR4 (162643), is first transiently downregulated before being significantly upregulated on stem cells after GCSF treatment, corresponding to the oscillations in GCSF and SDF1 levels. Posttransplantation treatment of nonobese diabetic SCID mice with antibodies to either CXCR4 or to SDF1 significantly blocks the egress of both mature cells and stem cells into peripheral blood. Petit et al. (2002) proposed that manipulation of SDF1-CXCR4 interactions may be an improved way to control the navigation of progenitor cells between the bone marrow and blood.
Levesque et al. (2003) demonstrated that the mobilization of HPCs by granulocyte colony-stimulating factor or cyclophosphamide was due to the disruption of the CXCR4/CXCL12 chemotactic pathway. The mobilization of HPCs coincided in vivo with the cleavage of the N terminus of the chemokine receptor CXCR4 found on HPCs. This resulted in the loss of chemotactic response of the HPCs to the CXCR4 ligand, CXCL12. The concentration of CXCL12 was also decreased in vivo in the bone marrow of mobilized mice, and this decrease coincided with the accumulation of serine proteases capable of direct cleavage and inactivation of CXCL12. As both CXCL12 and CXCR4 are essential for the homing and retention of HPCs in the bone marrow, the proteolytic degradation of CXCL12 and CXCR4 may represent a critical step in the mobilization of HPCs into the peripheral blood by GCSF or cyclophosphamide.
Using immunohistochemistry in neonatal rats, Harada et al. (2005) detected expression of the Csf3 receptor (CSF3R; 138971) on cardiomyocytes and cardiac fibroblasts and demonstrated activation of the Jak (see 147795)-Stat (see 600555) pathway in cardiomyocytes by Csf3. In a mouse model of myocardial infarction, Csf3 treatment did not affect initial infarct size at day 3 but improved cardiac function as early as 1 week postinfarction, and the beneficial effects were reduced by delayed start of treatment. Csf3 induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes, and Csf3 also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts. All of these effects of Csf3 were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. Harada et al. (2005) suggested that CSF3 promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through functional communication between cardiomyocytes and noncardiomyoctes.
By examining the effect of Gcsf administration in various mouse bone marrow transplantation (BMT) models, including gene deletion strains, Morris et al. (2009) found that exposure to Gcsf or pegylated Gcsf soon after BMT substantially increased graft-versus-host disease (GVHD; see 614395). This effect was dependent on total body irradiation (TBI) rendering host dendritic cells (DCs) responsive to Gcsf by upregulating Gcsfr. Stimulation of host DCs by Gcsf unleashed a cascade of events that included donor natural killer T-cell activation, Ifng (147570) secretion, and Cd40 (109535)-dependent amplification of donor cytotoxic T-cell function. The detrimental effects of Gcsf administration were observed only after TBI conditioning and when host antigen-presenting cells (APCs) were still present. Morris et al. (2009) proposed that these data help explain conflicting clinical studies from large European and North American BMT registries. They suggested that postponing GCSF administration after BMT until after the elimination of host APCs and without TBI-induced expression of donor DC GCSFR will avoid the detrimental effects of GCSF administration in allogeneic BMT recipients.
Schweizerhof et al. (2009) presented evidence that GCSF and GMCSF (CSF2; 138960) mediate bone cancer pain and tumor-nerve interactions. Increased levels of both factors were detected in bone marrow lysates and adjoining connective tissue in a mouse sarcoma model of bone tumor-induced pain compared to controls. The functional receptors GCSFR (CSF3R) and GMCSFR (CSF2RA; 306250) were expressed on peripheral nerves in the bone matrix and in dorsal root ganglia. GMCSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP (114130) release, and caused sprouting of sensory nerve endings in skin. RNA interference of GCSF and GMCSF signaling in the mouse sarcoma model led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain.
Harada, M., Qin, Y., Takano, H., Minamino, T., Zou, Y,, Toko, H., Ohtsuka, M., Matsuura, K., Sano, M., Nishi, J., Iwanaga, K., Akazawa, H., Kunieda, T., Zhu, W., Hasegawa, H., Kunisada, K., Nagai, T., Nakaya, H., Yamauchi-Takihara, K., Komuro, I. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nature Med. 11: 305-311, 2005. [PubMed: 15723072] [Full Text: https://doi.org/10.1038/nm1199]
Kanda, N., Fukushige, S., Murotsu, T., Yoshida, M. C., Tsuchiya, M., Asano, S., Kaziro, Y., Nagata, S. Human gene coding for granulocyte-colony stimulating factor assigned to the q21-q22 region of chromosome 17. Somat. Cell Molec. Genet. 13: 679-684, 1987. [PubMed: 3499671] [Full Text: https://doi.org/10.1007/BF01534488]
Le Beau, M. M., Lemons, R. S., Carrino, J. J., Pettenati, M. J., Souza, L. M., Diaz, M. O., Rowley, J. D. 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: 795-799, 1987. [PubMed: 3501046]
Levesque, J.-P., Hendy, J., Takamatsu, Y., Simmons, P. J., Bendall, L. J. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J. Clin. Invest. 111: 187-196, 2003. [PubMed: 12531874] [Full Text: https://doi.org/10.1172/JCI15994]
Metcalf, D. The granulocyte-macrophage colony-stimulating factors. Science 229: 16-22, 1985. [PubMed: 2990035] [Full Text: https://doi.org/10.1126/science.2990035]
Morris, E. S., MacDonald, K. P. A., Kuns, R. D., Morris, H. M., Banovic, T., Don, A. L. J., Rowe, V., Wilson, Y. A., Raffelt, N. C., Engwerda, C. R., Burman, A. C., Markey, K. A., Godfrey, D. I., Smyth, M. J., Hill, G. R. Induction of natural killer T cell-dependent alloreactivity by administration of granulocyte colony-stimulating factor after bone marrow transplantation. Nature Med. 15: 436-441, 2009. [PubMed: 19330008] [Full Text: https://doi.org/10.1038/nm.1948]
Nagata, S., Tsuchiya, M., Asano, S., Kaziro, Y., Yamazaki, T., Yamamoto, O., Hirata, Y., Kubota, N., Oheda, M., Nomura, H., Ono, M. Molecular cloning and expression of cDNA for the human granulocyte colony-stimulating factor. Nature 319: 415-418, 1986. [PubMed: 3484805] [Full Text: https://doi.org/10.1038/319415a0]
Nagata, S., Tsuchiya, M., Asano, S., Yamamoto, O., Hirata, Y., Kubota, N., Oheda, M., Nomura, H., Yamazaki, T. The chromosomal gene structure and two mRNAs for human granulocyte colony-stimulating factor. EMBO J. 5: 575-581, 1986. [PubMed: 2423327] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04249.x]
Petit, I., Szyper-Kravitz, M., Nagler, A., Lahav, M., Peled, A., Habler, L., Ponomaryov, T., Taichman, R. S., Arenzana-Seisdedos, F., Fujii, N., Sandbank, J., Zipori, D., Lapidot, T. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nature Immun. 3: 687-694, 2002. Note: Erratum: Nature Immun. 3: 787 only, 2002. [PubMed: 12068293] [Full Text: https://doi.org/10.1038/ni813]
Schweizerhof, M., Stosser, S., Kurejova, M., Njoo, C., Gangadharan, V., Agarwal, N., Schmelz, M., Bali, K. K., Michalski, C. W., Brugger, S., Dickenson, A., Simone, D. A., Kuner, R. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. (Letter) Nature Med. 15: 802-807, 2009. [PubMed: 19525966] [Full Text: https://doi.org/10.1038/nm.1976]
Simmers, R. N., Smith, J., Shannon, M. F., Wong, G., Lopez, A. F., Baker, E., Sutherland, G. R., Vadas, M. A. Localization of the human G-CSF gene to the region of a breakpoint in the translocation typical of acute promyelocytic leukemia. Hum. Genet. 78: 134-136, 1988. [PubMed: 2448221] [Full Text: https://doi.org/10.1007/BF00278182]
Souza, L. M., Boone, T. C., Gabrilove, J., Lai, P. H., Zsebo, K. M., Murdock, D. C., Chazin, V. R., Bruszewski, J., Lee, H., Chen, K. K., Barendt, J., Platzer, E., Moore, M. A. S., Mertelsmann, R., Welte, K. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science 232: 61-65, 1986. [PubMed: 2420009] [Full Text: https://doi.org/10.1126/science.2420009]
Sudo, S., Yamada, H., Kikuchi, K., Sumie, A., Yamashita, Y., Tumura, N., Kawaguchi, I., Fujimoto, S., Kato, A., Yamaguchi, J. A case of ovarian carcinoma with production of granulocyte colony-stimulating factor. Brit. J. Haemat. 92: 137-139, 1996. [PubMed: 8562385] [Full Text: https://doi.org/10.1046/j.1365-2141.1996.274811.x]
Tweardy, D. J., Cannizzaro, L. A., Palumbo, A. P., Shane, S., Huebner, K., Vantuinen, P., Ledbetter, D. H., Finan, J. B., Nowell, P. C., Rovera, G. 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: 209-220, 1987. [PubMed: 2453015]