Biology:CXCL1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils[1][2] or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay.[3] This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E (normal rat kidney-52E) cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC).[4] In humans, this protein is encoded by the gene Cxcl1 [5] and is located on human chromosome 4 among genes for other CXC chemokines.[6]

Structure and expression

CXCL1 exists as both monomer and dimer and both forms are able to bind chemokine receptor CXCR2.[7] However, CXCL1 chemokine is able to dimerize only at higher (micromolar) concentrations and its concentrations are only nanomolar or picomolar upon normal conditions, which means that the form of WT CXCL1 is more likely monomeric while dimeric CXCL1 is present only during infection or injury. CXCL1 monomer consists of three antiparallel β-strands followed by C- terminal α-helix and this α-helix together with the first β-strand are involved in forming a dimeric globular structure.[8]

Upon normal conditions, CXCL1 is not expressed constitutively. It's produced by a variety of immune cells such as macrophages, neutrophils and epithelial cells,[9][10] or Th17 population. Moreover, its expression can be also induced indirectly by IL-1, TNF-α or IL-17 produced again by Th17 cells [11] and is triggered mainly by activation of NF-κB or C/EBPβ signaling pathways predominantly involved in inflammation and leading to production of other inflammatory cytokines.[11]

Function

CXCL1 has a potentially similar role as interleukin-8 (IL-8/CXCL8). After binding to its receptor CXCR2, CXCL1 activates phosphatidylinositol-4,5-bisphosphate 3-kinase-γ (PI3Kγ)/Akt, MAP kinases such as ERK1/ERK2 or phospholipase-β (PLCβ) signaling pathways. CXCL1 is expressed at higher levels during inflammatory responses thus contributing to the process of inflammation.[12] CXCL1 is also involved in the processes of wound healing and tumorigenesis.[13][14][15]

Role in cancer

CXCL1 has a role in angiogenesis and arteriogenesis [16] and thus has been shown to act in the process of tumor progression. The role of CXCL1 was described by several studies in the development of various tumors, such as breast cancer, gastric and colorectal carcinoma or lung cancer.[17][18][19] Also, CXCL1 is secreted by human melanoma cells, has mitogenic properties and is implicated in melanoma pathogenesis.[20][21][22]

Role in nervous system and sensitization

CXCL1 plays a role in spinal cord development by inhibiting the migration of oligodendrocyte precursors.[7] CXCR2 receptor for CXCL1 is expressed in the brain and spinal cord by neurons and oligodendrocytes and during CNS pathologies such as Alzheimer's disease, multiple sclerosis and brain injury also by microglia. An initial study in mice showed evidence that CXCL1 decreased the severity of multiple sclerosis and may offer a neuro-protective function.[23] On the other hand, on the periphery, CXCL1 contributes to the release of prostaglandins and thus causes increased sensitivity to pain and drives nociceptive sensitization via recruitment of neutrophils to the tissue. Phosphorylation of ERK1/ERK2 kinases and activation of NMDA receptors leads to transcription of genes inducing chronic pain, such as c-Fos or cyclooxygenase-2 (COX-2).[12]

References

  1. ↑ "Neutrophil-activating properties of the melanoma growth-stimulatory activity". The Journal of Experimental Medicine 171 (5): 1797–1802. May 1990. doi:10.1084/jem.171.5.1797. PMID 2185333. 
  2. ↑ "High- and low-affinity binding of GRO alpha and neutrophil-activating peptide 2 to interleukin 8 receptors on human neutrophils". Proceedings of the National Academy of Sciences of the United States of America 89 (21): 10542–10546. November 1992. doi:10.1073/pnas.89.21.10542. PMID 1438244. Bibcode: 1992PNAS...8910542S. 
  3. ↑ "Molecular cloning of gene sequences regulated by platelet-derived growth factor". Cell 33 (3): 939–947. July 1983. doi:10.1016/0092-8674(83)90037-5. PMID 6872001. 
  4. ↑ "Purification and characterization of cytokine-induced neutrophil chemoattractant produced by epithelioid cell line of normal rat kidney (NRK-52E cell)". Biochemical and Biophysical Research Communications 161 (3): 1093–1099. June 1989. doi:10.1016/0006-291X(89)91355-7. PMID 2662972. 
  5. ↑ "Identification of three related human GRO genes encoding cytokine functions". Proceedings of the National Academy of Sciences of the United States of America 87 (19): 7732–7736. October 1990. doi:10.1073/pnas.87.19.7732. PMID 2217207. Bibcode: 1990PNAS...87.7732H. 
  6. ↑ "Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin". The EMBO Journal 7 (7): 2025–2033. July 1988. doi:10.1002/j.1460-2075.1988.tb03042.x. PMID 2970963. 
  7. ↑ 7.0 7.1 "The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration". Cell 110 (3): 373–383. August 2002. doi:10.1016/S0092-8674(02)00838-3. PMID 12176324. 
  8. ↑ "Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor". The Journal of Biological Chemistry 288 (17): 12244–12252. April 2013. doi:10.1074/jbc.m112.443762. PMID 23479735. 
  9. ↑ "Cloning and sequencing of a new gro transcript from activated human monocytes: expression in leukocytes and wound tissue". Molecular and Cellular Biology 10 (10): 5596–5599. October 1990. doi:10.1128/mcb.10.10.5596. PMID 2078213. 
  10. ↑ "Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages". The American Journal of Physiology 266 (3 Pt 1): L278–L286. March 1994. doi:10.1152/ajplung.1994.266.3.L278. PMID 8166297. 
  11. ↑ 11.0 11.1 "Th17 cells regulate the production of CXCL1 in breast cancer". International Immunopharmacology 56: 320–329. March 2018. doi:10.1016/j.intimp.2018.01.026. PMID 29438938. 
  12. ↑ 12.0 12.1 "CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization". Neurobiology of Disease 105: 109–116. September 2017. doi:10.1016/j.nbd.2017.06.001. PMID 28587921. 
  13. ↑ "Delayed wound healing in CXCR2 knockout mice". The Journal of Investigative Dermatology 115 (2): 234–244. August 2000. doi:10.1046/j.1523-1747.2000.00034.x. PMID 10951241. 
  14. ↑ "The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma". Journal of Leukocyte Biology 67 (1): 53–62. January 2000. doi:10.1002/jlb.67.1.53. PMID 10647998. [yes|permanent dead link|dead link}}]
  15. ↑ "Enhanced tumor-forming capacity for immortalized melanocytes expressing melanoma growth stimulatory activity/growth-regulated cytokine beta and gamma proteins". International Journal of Cancer 73 (1): 94–103. September 1997. doi:10.1002/(SICI)1097-0215(19970926)73:1<94::AID-IJC15>3.0.CO;2-5. PMID 9334815. 
  16. ↑ "CXCL1 promotes arteriogenesis through enhanced monocyte recruitment into the peri-collateral space". Angiogenesis 18 (2): 163–171. April 2015. doi:10.1007/s10456-014-9454-1. PMID 25490937. 
  17. ↑ "Complementary action of CXCL1 and CXCL8 in pathogenesis of gastric carcinoma". International Journal of Clinical and Experimental Pathology 11 (2): 1036–1045. 2018-02-01. PMID 31938199. 
  18. ↑ "Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1". International Journal of Molecular Sciences 19 (8): 2427. August 2018. doi:10.3390/ijms19082427. PMID 30115896. 
  19. ↑ "Role of CXC group chemokines in lung cancer development and progression". Journal of Thoracic Disease 9 (Suppl 3): S164–S171. April 2017. doi:10.21037/jtd.2017.03.61. PMID 28446981. 
  20. ↑ "Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells". Proceedings of the National Academy of Sciences of the United States of America 84 (20): 7188–7192. October 1987. doi:10.1073/pnas.84.20.7188. PMID 2890161. Bibcode: 1987PNAS...84.7188A. 
  21. ↑ "Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution". Journal of Cellular Biochemistry 36 (2): 185–198. February 1988. doi:10.1002/jcb.240360209. PMID 3356754. 
  22. ↑ "Role of CXCL1 in tumorigenesis of melanoma". Journal of Leukocyte Biology 72 (1): 9–18. July 2002. doi:10.1189/jlb.72.1.9. PMID 12101257. 
  23. ↑ "Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1". The American Journal of Pathology 174 (1): 164–176. January 2009. doi:10.2353/ajpath.2009.080350. PMID 19095949. 

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