Alternative titles; symbols
HGNC Approved Gene Symbol: CXCL1
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:73,869,393-73,871,308 (from NCBI)
Chemokines are a group of small (approximately 8 to 14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines. CXC chemokines are further subdivided into ELR and non-ELR types based on the presence or absence of a glu-leu-arg sequence adjacent and N terminal to the CXC motif. ELR types are chemotactic for neutrophils, while non-ELR types are chemotactic for lymphocytes (summary by Strieter et al., 1995; Zlotnik and Yoshie, 2000).
Melanoma growth stimulatory activity (MGSA) is a mitogenic polypeptide secreted by human melanoma cells. The mature form is maximally 73 amino acids long. MGSA is structurally related to the platelet-derived beta-thromboglobulin. It is the product of the gene GRO isolated by Anisowicz et al. (1987). Horuk et al. (1993) indicated that structurally MGSA belongs to a superfamily of proteins that includes interleukin-8 (IL8, or CXCR2; 146930) and platelet factor-4 (PF4; 173460). These proteins are involved in inflammatory processes.
Anisowicz et al. (1988) studied the expression of GRO in human foreskin fibroblasts and in mammary epithelial cells.
Tsai et al. (2002) demonstrated a role for rodent Cxcl1 and Cxcr2 in patterning the developing spinal cord. Signaling through Cxcr2, Cxcl1 inhibited oligodendrocyte precursor migration. The migrational arrest was rapid, reversible, and concentration dependent, and it reflected enhanced cell/substrate interactions. White matter expression of Cxcl1 was temporospatially regulated. Developing Cxcr2 null spinal cords contained reduced oligodendrocytes abnormally concentrated at the periphery. In mouse and rat slice preparations, Cxcl1 inhibited embryonic oligodendrocyte precursor migration, and widespread dispersal of postnatal precursors occurred in the absence of Cxcr2 signaling. The data suggested that a population of presumptive white matter by oligodendrocyte precursors is dependent on localized expression of CXCL1.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including CXCL1, were functionally validated. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Yang et al. (2006) found that GRO1 was activated by RAS (HRAS; 190020) and was vital for survival and malignant transformation of T29 and T80 immortalized human ovarian epithelial cell lines. GRO1 promoted senescence in ovarian stromal fibroblast cell lines, and this effect depended on functional p53 (TP53; 191170). GRO1 was secreted by slow-growing tumor-associated fibroblasts, but not by faster growing normal ovarian fibroblasts. Tumor-associated fibroblasts enhanced malignant transformation of T29 cells following injection into nude mice. GRO1 was expressed at significantly higher amounts in ovarian cancers than in normal tissues, and was higher in serum samples from women with ovarian cancer compared with those without. Yang et al. (2006) concluded that GRO1 alters the microenvironment of ovarian tumors by acting in an autocrine manner to maintain fibroblast senescence and GRO1 secretion and in a paracrine manner to promote tumorigenesis in ovarian epithelial cells.
Seifert et al. (2016) reported that the principal components of the necrosome, receptor-interacting proteins RIP1 (603453) and RIP3 (605817), are highly expressed in pancreatic ductal adenocarcinoma (PDA) and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment associated with intact RIP1/RIP3 signaling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SF3B3 (605592), a subunit of the histone deacetylase complex, was expressed in PDA in a RIP1/RIP3-dependent manner, and MINCLE (609962), its cognate receptor, was upregulated in tumor-infiltrating myeloid cells. Ligation of MINCLE by SF3B3 promoted oncogenesis, whereas deletion of MINCLE protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumor microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or MINCLE is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or MINCLE signaling, were reprogrammed into indispensable mediators of antitumor immunity in the absence of RIP3 or MINCLE. Seifert et al. (2016) concluded that their work described parallel networks of necroptosis-induced CXCL1 and MINCLE signaling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.
Richmond et al. (1988) mapped the MGSA gene to 4q13-q21 by a combination of somatic cell and in situ hybridization. They pointed out that PF4 maps to the same region and that piebald trait (172800), a pigment anomaly, may also be coded there. Anisowicz et al. (1988) demonstrated by in situ hybridization that the GRO gene is on 4q21 in the human and on 1p5 in the Chinese hamster. Sakaguchi et al. (1989) demonstrated that the Mgsa locus in the mouse is on chromosome 5. Several genes affecting skin pigmentation are located on mouse chromosome 5.
By PCR analysis and mapping of YAC clones, O'Donovan et al. (1999) localized a number of CXC chemokine genes to 4q12-q21. They proposed that the order in this region is centromere--IL8--GRO1/PPBP (121010)/PF4--SCYB5 (600324)/SCYB6 (138965)--GRO2 (139110)/GRO3 (139111)--SCYB11 (604852)--SCYB10 (147310)--MIG (601704)--telomere. The GRO1 gene was localized to 4q12-q13.
In matrilysin (MMP7; 178990)-null mice, Li et al. (2002) found that neutrophils remained confined in the interstitium of injured lungs and did not advance into the alveolar space. Impaired transepithelial migration was accompanied by a lack of both shed syndecan-1 (SDC1; 186355), a heparan sulfate proteoglycan, and Cxcl1 in the alveolar fluid. Cxcl1 was bound to shed Sdc1, and it was not detected in the lavage of Sdc1 null mice. In vitro, Mmp7 cleaved Sdc1 from the surface of cells. The authors concluded that MMP7-mediated shedding of SDC1/CXCL1 complexes from the mucosal surface directs and confines neutrophil influx to sites of injury.
In response to herpes simplex virus (HSV)-1 infection, corneal epithelial cells produce CXCL1 and IL6 (147620). To determine if these factors both play a role in recurrent stromal keratitis, West et al. (2014) treated mice with anti-Cxcl1 or anti-Il6. Mice treated with anti-Cxcl1, but not those treated with anti-Il6, initially showed increased virus production in cornea following ultraviolet B-induced reactivation, but they eventually exhibited viral clearance and disappearance of recurrent keratitis. The mice treated with anti-Cxcl1 also had significantly fewer infiltrating neutrophils. Studies of mice lacking Cxcr2 (146928), the primary receptor for Cxcl1, and mice deficient in Il6 supported the antibody results. West et al. (2014) concluded that CXCL1 is the major inflammatory factor in recurrent herpetic stromal keratitis.
Anisowicz, A., Bardwell, L., Sager, R. Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells. Proc. Nat. Acad. Sci. 84: 7188-7192, 1987. [PubMed: 2890161] [Full Text: https://doi.org/10.1073/pnas.84.20.7188]
Anisowicz, A., Zajchowski, D., Stenman, G., Sager, R. Functional diversity of GRO gene expression in human fibroblasts and mammary epithelial cells. Proc. Nat. Acad. Sci. 85: 9645-9649, 1988. [PubMed: 3264403] [Full Text: https://doi.org/10.1073/pnas.85.24.9645]
Horuk, R., Yansura, D. G., Reilly, D., Spencer, S., Bourell, J., Henzel, W., Rice, G., Unemori, E. Purification, receptor binding analysis, and biological characterization of human melanoma growth stimulating activity (MGSA): evidence for a novel MGSA receptor. J. Biol. Chem. 268: 541-546, 1993. [PubMed: 8380167]
Li, Q., Park, P. W., Wilson, C. L., Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111: 635-646, 2002. [PubMed: 12464176] [Full Text: https://doi.org/10.1016/s0092-8674(02)01079-6]
Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., Massague, J. Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005. [PubMed: 16049480] [Full Text: https://doi.org/10.1038/nature03799]
O'Donovan, N., Galvin, M., Morgan, J. G. Physical mapping of the CXC chemokine locus on human chromosome 4. Cytogenet. Cell Genet. 84: 39-42, 1999. [PubMed: 10343098] [Full Text: https://doi.org/10.1159/000015209]
Richmond, A., Balentien, E., Thomas, H. G., Flaggs, G., Barton, D. E., Spiess, J., Bordoni, R., Francke, U., Derynck, R. Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin. EMBO J. 7: 2025-2033, 1988. [PubMed: 2970963] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03042.x]
Sakaguchi, A. Y., Lalley, P. A., Ghosh Choudhury, G., Martinez, L., Han, E. S., Killary, A. M., Naylor, S. L., Wang, L.-M. Mouse melanoma growth stimulatory activity gene (Mgsa) is polymorphic and syntenic with the W, Patch, Rumpwhite, and recessive spotting loci on chromosome 5. Genomics 5: 629-632, 1989. [PubMed: 2575589] [Full Text: https://doi.org/10.1016/0888-7543(89)90033-5]
Seifert, L., Werba, G., Tiwari, S., Giao Ly, N. N., Alothman, S., Alqunaibit, D., Avanzi, A., Barilla, R., Daley, D., Greco, S. H., Torres-Hernandez, A., Pergamo, M., and 10 others. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532: 245-249, 2016. Note: Erratum: Nature 591: E28, 2021. [PubMed: 27049944] [Full Text: https://doi.org/10.1038/nature17403]
Strieter, R. M., Polverini, P. J., Arenberg, D. A., Kunkel, S. L. The role of CXC chemokines as regulators of angiogenesis. Shock 4: 155-160, 1995. [PubMed: 8574748] [Full Text: https://doi.org/10.1097/00024382-199509000-00001]
Tsai, H.-H., Frost, E., To, V., Robinson, S., ffrench-Constant, C., Geertman, R., Ransohoff, R. M., Miller, R. H. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110: 373-383, 2002. [PubMed: 12176324] [Full Text: https://doi.org/10.1016/s0092-8674(02)00838-3]
West, D. M., Del Rosso, C. R., Yin, X.-T., Stuart, P. M. CXCL1 but not IL-6 is required for recurrent herpetic stromal keratitis. J. Immun. 192: 1762-1767, 2014. [PubMed: 24442436] [Full Text: https://doi.org/10.4049/jimmunol.1302957]
Yang, G., Rosen, D. G., Zhang, Z., Bast, R. C., Jr., Mills, G. B., Colacino, J. A., Mercado-Uribe, I., Liu, J. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Nat. Acad. Sci. 103: 16472-16477, 2006. [PubMed: 17060621] [Full Text: https://doi.org/10.1073/pnas.0605752103]
Zlotnik, A., Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12: 121-127, 2000. [PubMed: 10714678] [Full Text: https://doi.org/10.1016/s1074-7613(00)80165-x]