CXCL1

CXCL1
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1MGS, 1MSG, 1MSH
Identifikatori
Aliasi	CXCL1
Vanjski ID-jevi	OMIM: 155730 MGI: 1340094 HomoloGene: 136748 GeneCards: CXCL1
Lokacija gena (čovjek) Hrom. Hromosom 4 (čovjek)[1] Bend 4q13.3 Početak 73,869,393 bp[1] Kraj 73,871,308 bp[1]
Lokacija gena (miš) Hrom. Hromosom 5 (miš)[2] Bend 5 E1|5 44.78 cM Početak 91,051,730 bp[2] Kraj 91,053,797 bp[2]
Ontologija gena Molekularna funkcija • signaling receptor binding • growth factor activity • cytokine activity • GO:0010577 enzyme activator activity • CXCR chemokine receptor binding • chemokine activity Ćelijska komponenta • extracellular region • Vanćelijsko • specific granule lumen • tertiary granule lumen Biološki proces • negative regulation of cell population proliferation • GO:0007243 intracellular signal transduction • response to lipopolysaccharide • GO:0072468 Transdukcija signala • G protein-coupled receptor signaling pathway • nervous system development • positive regulation of neutrophil chemotaxis • Ćelijska proliferacija • actin cytoskeleton organization • GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor • chemokine-mediated signaling pathway • GO:0048554 positive regulation of catalytic activity • cell chemotaxis • Hemotaksija • defense response • inflammatory response • neutrophil degranulation • antimicrobial humoral immune response mediated by antimicrobial peptide • regulation of signaling receptor activity • cytokine-mediated signaling pathway • neutrophil chemotaxis • leukocyte chemotaxis • cellular response to lipopolysaccharide Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	2919	20310
Ensembl	ENSG00000163739	ENSMUSG00000058427
UniProt	P09341	P10889
RefSeq (mRNK)	NM_001511	NM_009140
RefSeq (bjelančevina)	NP_001502	NP_033166
Lokacija (UCSC)	Chr 4: 73.87 – 73.87 Mb	Chr 5: 91.05 – 91.05 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Hemokinski ligand 1 (C-X-C motiv) jest mali peptid koji je kod ljudi kodiran genom CXCL1 sa hromosoma 4. Pripada porodici CXC hemokina idjeluje kao hemoatraktant za nekoliko imunskih ćelija, posebno neutrofil ^[5][6] ili drugih nehematopoetskih ćelija do mjesta ozljede ili infekcije i ima važnu ulogu u regulaciji imunskkih i upalnih odgovora. ]Ranije se zvao GRO1 onkogen, GROα, protein koji aktivira neutrofile 3 (NAP-3) i aktivnost stimulacije rasta melanoma alfa (MGSA-α). Poznat je i kao hemokin (KC) izveden iz keratinocita (KC) kod miševa ili neutrofilni hemoatraktant induciran citokinom tip-1 (CINC-1) kod pacova;^[7] na hromosomu 4 nalazi se među genima za ostale hemokine CXC.^[8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 107 aminokiselina, а molekulska težina 11.301 Da.^[9]

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

10		20		30		40		50
MARAALSAAP		SNPRLLRVAL		LLLLLVAAGR		RAAGASVATE		LRCQCLQTLQ
GIHPKNIQSV		NVKSPGPHCA		QTEVIATLKN		GRKACLNPAS		PIVKKIIEKM
LNSDKSN

Struktura i ekspresija

CXCL1 postoji i kao monomer i kao dimer, a oba oblika mogu vezati receptor hemokinski CXCR2.^[10] Međutim, hemokin CXCL1 može dimerizirati samo pri višim (mikromolnim) koncentracijama i njegove koncentracije su samo nanomolne ili pikomolne u normalnim uvjetima, što znači da je oblik WT CXCL1 vjerovatnije monomeran, dok je dimerni CXCL1 prisutan samo tokom infekcije ili ozljede. Monomer CXCL1 sastoji se od tri antiparalelna β-nizovi nakon kojih slijedi C-terminalni α-helika, a ovi α-heliksa zajedno s prvim β-listom uključeni su u formiranje dimerne globule struktura.^[11]

U normalnim uslovima, CXCL1 se ne eksprimira konstitutivno. Proizvode ga različite imunske ćelije kao što su makrofagi, neutrofili i epitelne ćelije,^[12][13] ili populacija Th17. Štaviše, njegovu ekspresiju mogu indirektno inducirati IL-1, TNF-α ili IL-17 koje ponovo proizvode Th17-ćelije ^[14] i pokreće se uglavnom aktivacijom NF-κB ili C/EBPβ signalnih puteva koji su pretežno uključeni u upale i dovode do proizvodnje drugih upalnih citokina.^[14]

Funkcija

CXCL1 ima potencijalno sličnu ulogu kao interleukin-8 (IL-8/CXCL8). Nakon vezivanja za svoj receptor CXCR2, CXCL1 aktivira fosfatidilinozitol-4,5-bisfosfat 3-kinaza-γ (PI3Kγ)/Akt, MAP kinaze kao što je ERK1/ERK2 ili fosfolipaza-β (PLCβ) signalne puteve. CXCL1 se eksprimira na višim nivoima tokom upalnih odgovora čime doprinosi procesu upale.^[15] CXCL1 je također uključen u procese zacjeljivanja rana i tumorigeneze.^[16][17][18]

Klinički značaj

CXCL1 ima ulogu u angiogenezi i arteriogenezi ^[19] i tako se pokazalo da djeluje u procesu progresije tumora. Uloga CXCL1 opisana je u nekoliko studija u razvoju različitih tumora, kao što su rak dojke, želuca i debelog crijeva ili pluća.^[20][21][22] Također, CXCL1 luče ćelije ljudskog melanoma, ima mitogena svojstva i uključen je u patogenezu melanoma.^[23][24][25]

Uloga u nervnom sistemu i senzibilizaciji

CXCL1 ima ulogu u razvoju kičmene moždine, inhibirajući migraciju prekursora oligodendrocita.^[10] Receptor CXCR2-a za CXCL1 se eksprimira u mozgu i kičmenoj moždini pomoću neurona i oligodendrocita te tokom patologija centralnog nervnog sistema ka o što su Alzheimerova bolest, multipla skleroza i ozljeda mozga također zbog mikroglije. Inicijalna studija na miševima dala je dokaze da CXCL1 smanjuje težinu multiple skleroze i može ponuditi neurozaštitnu funkciju.^[26] S druge strane, na periferiji, CXCL1 doprinosi oslobađanju prostaglandina i na taj način uzrokuje povećanu osjetljivost na bol i pokreće nociceptivnu senzibilizaciju putem regrutacije neutrofila u tkivo. Fosforilacija ERK1/ERK2-kinaza i aktivacija NMDA receptora dovodi do transkripcije gena koji izazivaju hroničnu bol, kao što su c-Fos ili ciklooksigenaza-2 (COX-2).^[15]

Reference

1. GRCh38: Ensembl release 89: ENSG00000163739 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000058427 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Moser B, Clark-Lewis I, Zwahlen R, Baggiolini M (maj 1990). "Neutrophil-activating properties of the melanoma growth-stimulatory activity". The Journal of Experimental Medicine. 171 (5): 1797–802. doi:10.1084/jem.171.5.1797. PMC 2187876. PMID 2185333.
6. Schumacher C, Clark-Lewis I, Baggiolini M, Moser B (novembar 1992). "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): 10542–6. Bibcode:1992PNAS...8910542S. doi:10.1073/pnas.89.21.10542. PMC 50375. PMID 1438244.
7. Haskill S, Peace A, Morris J, Sporn SA, Anisowicz A, Lee SW, et al. (oktobar 1990). "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): 7732–6. Bibcode:1990PNAS...87.7732H. doi:10.1073/pnas.87.19.7732. PMC 54822. PMID 2217207.
8. Richmond A, Balentien E, Thomas HG, Flaggs G, Barton DE, Spiess J, et al. (juli 1988). "Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin". The EMBO Journal. 7 (7): 2025–33. doi:10.1002/j.1460-2075.1988.tb03042.x. PMC 454478. PMID 2970963.
9. "UniProt, P09341" (jezik: engleski). Pristupljeno 23. 10. 2021.
10. Tsai HH, Frost E, To V, Robinson S, Ffrench-Constant C, Geertman R, et al. (august 2002). "The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration". Cell. 110 (3): 373–83. doi:10.1016/S0092-8674(02)00838-3. PMID 12176324. S2CID 16880392.
11. Ravindran A, Sawant KV, Sarmiento J, Navarro J, Rajarathnam K (april 2013). "Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor". The Journal of Biological Chemistry. 288 (17): 12244–52. doi:10.1074/jbc.m112.443762. PMC 3636908. PMID 23479735.
12. Iida N, Grotendorst GR (oktobar 1990). "Cloning and sequencing of a new gro transcript from activated human monocytes: expression in leukocytes and wound tissue". Molecular and Cellular Biology. 10 (10): 5596–9. doi:10.1128/mcb.10.10.5596. PMC 361282. PMID 2078213.
13. Becker S, Quay J, Koren HS, Haskill JS (mart 1994). "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): L278-86. doi:10.1152/ajplung.1994.266.3.L278. PMID 8166297.
14. Ma K, Yang L, Shen R, Kong B, Chen W, Liang J, et al. (mart 2018). "Th17 cells regulate the production of CXCL1 in breast cancer". International Immunopharmacology. 56: 320–329. doi:10.1016/j.intimp.2018.01.026. PMID 29438938. S2CID 3568978.
15. Silva RL, Lopes AH, Guimarães RM, Cunha TM (septembar 2017). "CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization". Neurobiology of Disease. 105: 109–116. doi:10.1016/j.nbd.2017.06.001. PMID 28587921. S2CID 4916646.
16. Devalaraja RM, Nanney LB, Du J, Qian Q, Yu Y, Devalaraja MN, Richmond A (august 2000). "Delayed wound healing in CXCR2 knockout mice". The Journal of Investigative Dermatology. 115 (2): 234–44. doi:10.1046/j.1523-1747.2000.00034.x. PMC 2664868. PMID 10951241.
17. Haghnegahdar H, Du J, Wang D, Strieter RM, Burdick MD, Nanney LB, et al. (januar 2000). "The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma". Journal of Leukocyte Biology. 67 (1): 53–62. doi:10.1002/jlb.67.1.53. PMC 2669312. PMID 10647998.^{[trajno mrtav link]}
18. Owen JD, Strieter R, Burdick M, Haghnegahdar H, Nanney L, Shattuck-Brandt R, Richmond A (septembar 1997). "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. doi:10.1002/(SICI)1097-0215(19970926)73:1<94::AID-IJC15>3.0.CO;2-5. PMID 9334815.
19. Vries MH, Wagenaar A, Verbruggen SE, Molin DG, Dijkgraaf I, Hackeng TH, Post MJ (april 2015). "CXCL1 promotes arteriogenesis through enhanced monocyte recruitment into the peri-collateral space". Angiogenesis. 18 (2): 163–71. doi:10.1007/s10456-014-9454-1. PMID 25490937. S2CID 52835567.
20. Chen X, Jin R, Chen R, Huang Z (1. 2. 2018). "Complementary action of CXCL1 and CXCL8 in pathogenesis of gastric carcinoma". International Journal of Clinical and Experimental Pathology. 11 (2): 1036–1045. PMC 6958037. PMID 31938199.
21. Hsu YL, Chen YJ, Chang WA, Jian SF, Fan HL, Wang JY, Kuo PL (august 2018). "Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1". International Journal of Molecular Sciences. 19 (8): 2427. doi:10.3390/ijms19082427. PMC 6121631. PMID 30115896.
22. Spaks A (april 2017). "Role of CXC group chemokines in lung cancer development and progression". Journal of Thoracic Disease. 9 (Suppl 3): S164–S171. doi:10.21037/jtd.2017.03.61. PMC 5392545. PMID 28446981.
23. Anisowicz A, Bardwell L, Sager R (oktobar 1987). "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): 7188–92. Bibcode:1987PNAS...84.7188A. doi:10.1073/pnas.84.20.7188. PMC 299255. PMID 2890161.
24. Richmond A, Thomas HG (februar 1988). "Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution". Journal of Cellular Biochemistry. 36 (2): 185–98. doi:10.1002/jcb.240360209. PMID 3356754. S2CID 10674236.
25. Dhawan P, Richmond A (juli 2002). "Role of CXCL1 in tumorigenesis of melanoma". Journal of Leukocyte Biology. 72 (1): 9–18. PMC 2668262. PMID 12101257.
26. Omari KM, Lutz SE, Santambrogio L, Lira SA, Raine CS (januar 2009). "Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1". The American Journal of Pathology. 174 (1): 164–76. doi:10.2353/ajpath.2009.080350. PMC 2631329. PMID 19095949.

Vanjski linkovi

• Lokacija ljudskog genoma CXCL1 i stranica sa detaljima o genu CXCL1 u UCSC Genome Browseru.

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