View source for Stromal cell-derived factor 1

{{Short description|Mammalian protein found in Homo sapiens}}
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{{Infobox gene}}
The '''stromal cell-derived factor 1''' ('''SDF-1'''), also known as '''C-X-C motif chemokine 12''' (CXCL12), is a [[chemokine]] [[protein]] that in humans is encoded by the ''CXCL12'' [[gene]] on [[chromosome 10]].<ref name="entrez"/> It is ubiquitously expressed in many tissues and cell types.<ref>{{Cite web|url=http://biogps.org/#goto=genereport&id=6387|title=BioGPS - your Gene Portal System|website=biogps.org|access-date=2016-10-11}}</ref> Stromal cell-derived factors 1-alpha and 1-beta are small cytokines that belong to the [[chemokine]] family, members of which activate [[leukocyte]]s and are often induced by proinflammatory stimuli such as [[lipopolysaccharide]], [[tumor necrosis factors|TNF]], or [[interleukin 1|IL1]]. The chemokines are characterized by the presence of 4 conserved [[cysteine]]s that form 2 [[disulfide bond]]s. They can be classified into 2 subfamilies. In the [[CC chemokine|CC subfamily]], the cysteine residues are adjacent to each other. In the [[CXC chemokine|CXC subfamily]], they are separated by an intervening amino acid. The SDF1 proteins belong to the latter group.<ref name="entrez"/> CXCL12 signaling has been observed in several cancers.<ref name = "Guo_2016" /><ref name = "Sorrentino_2016" /> The ''CXCL12'' gene also contains one of 27 [[SNPs]] associated with increased risk of [[coronary artery disease]].<ref name = "Mega_2015"  />
== Structure ==
=== Gene ===
The ''CXCL12'' gene resides on chromosome 10 at the band 10q11.21 and contains 4 [[exon|exons.]].<ref>{{Cite web |title=CXCL12 gene information - The Human Protein Atlas |url=https://www.proteinatlas.org/ENSG00000107562-CXCL12/summary/gene |access-date=2024-03-20 |website=www.proteinatlas.org}}</ref> This gene produces 7 [[isoforms]] through [[alternative splicing]].<ref name="UniProt">{{cite web | url = https://www.uniprot.org/uniprot/P48061 | title=CXCL12 - Stromal cell-derived factor 1 precursor - Homo sapiens (Human) - CXCL12 gene & protein | work = [[UniProt]] }}</ref>
=== Protein ===
This protein belongs to the [[intercrine]] alpha ([[chemokine]] CXC) family.<ref name="UniProt" /> SDF-1 is produced in two forms, SDF-1α/CXCL12a and SDF-1β/CXCL12b, by alternate splicing of the same gene.<ref name="De_La_Luz_Sierra_2004" /> Chemokines are characterized by the presence of four conserved [[cysteine]]s, which form two [[disulfide bonds]]. The CXCL12 proteins belong to the group of CXC chemokines, whose initial pair of cysteines are separated by one intervening [[amino acid]]. In addition, the first 8 residues of the CXCL12 [[N-terminus|N-terminal]] serve as a [[Receptor (biochemistry)|receptor]] binding site, though only Lys-1 and Pro-2 directly participated in activating the receptor. Meanwhile, the RFFESH motif (residues 12-17) in the loop region function as a docking site for CXCL12 receptor binding.<ref name = "Crump_1997" />
== Function ==
CXCL12 is expressed in many tissues in mice including [[brain]], [[thymus]], [[heart]], [[lung]], [[liver]], [[kidney]], [[spleen]], [[platelet]]s and [[bone marrow]].<ref name="Schrader_2002"/><ref>{{cite journal | vauthors = Custo S, Baron B, Felice A, Seria E |title=A comparative profile of total protein and six angiogenically-active growth factors in three platelet products |journal=GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW |date=5 July 2022 |volume=11 |issue=Doc06 |pages=Doc06 |doi=10.3205/iprs000167 |url=https://www.egms.de/static/en/journals/iprs/2022-11/iprs000167.shtml#block5 |pmid=35909816 |pmc=9284722}}</ref> CXCL12 is strongly [[chemotactic]] for [[lymphocyte]]s.<ref name="Bleul_1996"/><ref name="Ara_2003"/><ref name="Askari_2003"/><ref name="Ma_1998"/> During embryogenesis, it directs the migration of [[Haematopoiesis|hematopoietic]] cells from fetal [[liver]] to [[bone marrow]] and the formation of large blood vessels. It has also been shown that CXCL12 signalling regulates the expression of CD20 on B cells. CXCL12 is also chemotactic for [[mesenchymal stem cells]] and is expressed in the area of inflammatory bone destruction, where it mediates their suppressive effect on [[Osteoclastoma|osteoclastogenesis]].<ref name="Takano_2014"/>
In adulthood, CXCL12 plays an important role in [[angiogenesis]] by recruiting endothelial progenitor cells (EPCs) from the bone marrow through a CXCR4 dependent mechanism.<ref name="Zheng_2007"/>
[[CXCR4]], previously called LESTR or fusin, is the receptor for CXCL12.<ref name = "Bleul_1996"/> This CXCL12-CXCR4 interaction used to be considered exclusive (unlike for other chemokines and their receptors), but recently, it was suggested that CXCL12 may also bind the [[CXC chemokine receptors#CXCR7|CXCR7 receptor]] (now called ACKR3).<ref name="Balabanian_2005"/><ref name="Burns_2006"/><ref name="Cruz-Orengo_2011" /> By blocking CXCR4, a major coreceptor for HIV-1 entry, CXCL12 acts as an endogenous inhibitor of CXCR4-tropic HIV-1 strains.<ref name="Oberlin_1996"/>
=== CNS ===
During embryonic development, CXCL12 plays a role in cerebellar formation through the migration of neurons.<ref name="Bajetto_2001">{{cite journal | vauthors = Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G | title = Chemokines and their receptors in the central nervous system | journal = Frontiers in Neuroendocrinology | volume = 22 | issue = 3 | pages = 147–84 | date = July 2001 | pmid = 11456467 | doi = 10.1006/frne.2001.0214 | s2cid = 29689159 }}</ref> Within the CNS, CXCL12 contributes to cell proliferation, neurogenesis (nervous tissue development and growth), as well as neuroinflammation. Neural progenitor cells (NPCs) are stem cells that differentiate into glial and neuronal cells. CXCL12 promotes their migration to lesion sites within the brain, specifically over extensive ranges. Once at the site of damage, NPCs may begin stem cell based tissue repair to the lesion.<ref name="Li_2012">{{cite journal | vauthors = Li M, Hale JS, Rich JN, Ransohoff RM, Lathia JD | title = Chemokine CXCL12 in neurodegenerative diseases: an SOS signal for stem cell-based repair | journal = Trends in Neurosciences | volume = 35 | issue = 10 | pages = 619–28 | date = October 2012 | pmid = 22784557 | pmc = 3461091 | doi = 10.1016/j.tins.2012.06.003 }}</ref> The CXCL12/CXCR4 axis provides guidance cues for axons and neurites hence promoting neurite outgrowth (neurons forming projections) and neurogenesis.<ref name="pmid24639628">{{cite journal | vauthors = Guyon A | title = CXCL12 chemokine and its receptors as major players in the interactions between immune and nervous systems | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 65 | date = March 2014 | pmid = 24639628 | pmc = 3944789 | doi = 10.3389/fncel.2014.00065 | doi-access = free }}</ref> Like other chemokines, CXCL12 is involved with cell migration that contributes to inflammation. In regards to the CNS, CXCL12 plays a role in neuroinflammation by attracting leukocytes across the blood brain barrier.<ref name="Li_2012" /> however, excessive production and accumulation of CXCL12 can become toxic and the inflammation produced may result in serious consequences.<ref name="Guyon_2014">{{cite journal | vauthors = Guyon A | title = CXCL12 chemokine and its receptors as major players in the interactions between immune and nervous systems | journal = Frontiers in Cellular Neuroscience | volume = 8 | pages = 65 | date = 2014 | pmid = 24639628 | pmc = 3944789 | doi = 10.3389/fncel.2014.00065 | doi-access = free }}</ref>
== Clinical significance ==
In humans, CXCL12 has been implicated in a wide variety of biomedical conditions involving several organ systems.<ref name = "Pozzobon_2016" />  Furthermore, CXCL12 signaling in conjunction with CXCR7 signaling has been implicated in the progression of pancreatic cancer.<ref name="Guo_2016"/> In the urinary tract system, methylation of the CXCL12 promoter and expression of PD-L1 may be powerful prognostic biomarkers for biochemical recurrence in prostate carcinoma patients after radical prostatectomy, and further studies are ongoing to confirm if CXCL12 methylation may aid in active surveillance strategies.<ref>{{cite journal | vauthors = Goltz D, Holmes EE, Gevensleben H, Sailer V, Dietrich J, Jung M, Röhler M, Meller S, Ellinger J, Kristiansen G, Dietrich D | title = CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients | journal = Oncotarget | volume = 7 | issue = 33 | pages = 53309–53320 | date = July 2016 | pmid = 27462860 | pmc = 5288188 | doi = 10.18632/oncotarget.10786 }}</ref> In the field of oncology, melanoma associated fibroblasts are stimulated by stimulation of the A2B adenosine receptor followed by stimulation of fibroblast growth factor and increased expression of CXCL12.<ref name="Sorrentino_2016"/>
=== Clinical marker ===
A multi-locus genetic risk score study based on a combination of 27 loci, including the CXCL12 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).<ref name="Mega_2015"/>
=== Multiple Sclerosis ===
A neurological condition that results from a faulty interaction between the immune and nervous systems in [[multiple sclerosis]]. MS is characterized by demyelination of nerves due to the body's immune system attacking the CNS. Elevated levels of CXCL12 are observed in the cerebral spinal fluid of patients with MS. CXCL12 crosses the [[blood–brain barrier]] and causes [[neuroinflammation]] that contributes to axonal damage and therefore the progression of multiple sclerosis.<ref name="Krumbholz_2006">{{cite journal | vauthors = Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisäkk P, Ransohoff RM, Hofbauer M, Farina C, Derfuss T, Hartle C, Newcombe J, Hohlfeld R, Meinl E | title = Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment | journal = Brain: A Journal of Neurology | volume = 129 | issue = Pt 1 | pages = 200–11 | date = January 2006 | pmid = 16280350 | doi = 10.1093/brain/awh680 | doi-access = free }}</ref>{{Unreliable medical source|date=February 2018|sure=y}}
=== Alzheimer's disease ===
Though CXCL12 may be detrimental for those with MS, recent research is suggesting that this chemokine may be beneficial in decreasing the progression of patients with Alzheimer's. Alzheimer's is another neurological condition and the most common form of dementia where cognition significantly declines. One main characteristic of Alzheimer's is the accumulation of a brain plaque known as beta-amyloid. There are neuroprotective aspects of CXCL12 in mice with these plaques/Alzheimer's. PAK is a protein associated with maintaining dendritic spines, which are essential at synapses in receiving information from axons. Mislocalization of PAK occurs in patients with Alzheimer's, however pretreatment of neurons in mice with CXCL12 showed a suppression of that mislocalization.<ref name="Raman_2011">{{cite journal | vauthors = Raman D, Milatovic SZ, Milatovic D, Splittgerber R, Fan GH, Richmond A | title = Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity | journal = Toxicology and Applied Pharmacology | volume = 256 | issue = 3 | pages = 300–13 | date = November 2011 | pmid = 21704645 | pmc = 3236026 | doi = 10.1016/j.taap.2011.06.006 | bibcode = 2011ToxAP.256..300R }}</ref>{{Unreliable medical source|date=February 2018|sure=y}} Additionally, this pretreatment with CXCL decreased the prevalence of apoptosis and oxidative damage normally caused by the presence of the beta-amyloid plaque.<ref name="Raman_2011" />
===As a drug target===
Chemokines and chemokine receptors, of which CXCR stands out, regulate multiple processes such as morphogenesis, angiogenesis, and immune responses and are considered potential targets for drug development. It is indicated by clinical samples that a high expression level of CXCR4 in [[idiopathic pulmonary fibrosis]] lungs. Experimental evidence further indicate that CXCR4/CXCR12 is associated with the pathogenesis of lung fibrosis.<ref>{{cite journal | vauthors = Li F, Xu X, Geng J, Wan X, Dai H | title = The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity | journal = Experimental and Therapeutic Medicine | volume = 19 | issue = 3 | pages = 1844–1854 | date = March 2020 | pmid = 32104240 | pmc = 7027131 | doi = 10.3892/etm.2020.8433 }}</ref> In the gastrointestinal tract system, the CXCL12-CXCR4 axis is under investigation as an anti-fibrotic therapy in the treatment for chronic pancreatitis.<ref name = "Neesse_2016" /> For instance, blocking [[CXCR4]], the receptor for CXCL12, with [[Plerixafor]] (AMD-3100) increased the effectiveness of combretastatin in a mouse model of breast cancer, presumably by preventing macrophages from being recruited to tumours.[[Stromal cell-derived factor 1#cite note-pmid21490397-15|[15]]][[Stromal cell-derived factor 1#cite note-16|[16]]] AMD-3100 is also widely used in combination with G-CSF for mobilizing hematopoietic stem cells into the blood stream, allowing collection for [[bone marrow transplant]].<ref>De Clercq E. (2019) Mozobil(R) (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir Chem Chemother 27:1.</ref>
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<ref name="De_La_Luz_Sierra_2004">{{cite journal | vauthors = De La Luz Sierra M, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R, Zhang HH, Fales H, Tosato G | title = Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity | journal = Blood | volume = 103 | issue = 7 | pages = 2452–9 | date = April 2004 | pmid = 14525775 | doi = 10.1182/blood-2003-08-2857 | doi-access = free }}</ref>
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<ref name="entrez">{{cite web | title = Entrez Gene: CXCL12 chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1) | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6387 }}</ref>
<ref name = "Guo_2016">{{cite journal | vauthors = Guo JC, Li J, Zhou L, Yang JY, Zhang ZG, Liang ZY, Zhou WX, You L, Zhang TP, Zhao YP | title = CXCL12-CXCR7 axis contributes to the invasive phenotype of pancreatic cancer | journal = Oncotarget | volume = 7 | issue = 38 | pages = 62006–62018 | date = August 2016 | pmid = 27542220 | pmc = 5308707 | doi = 10.18632/oncotarget.11330 }}</ref>
<ref name="Ma_1998">{{cite journal | vauthors = Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA | title = Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 16 | pages = 9448–53 | date = August 1998 | pmid = 9689100 | pmc = 21358 | doi = 10.1073/pnas.95.16.9448 | bibcode = 1998PNAS...95.9448M | doi-access = free }}</ref>
<ref name = "Mega_2015" >{{cite journal | vauthors = Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS | title = Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials | journal = Lancet | volume = 385 | issue = 9984 | pages = 2264–71 | date = June 2015 | pmid = 25748612 | doi = 10.1016/S0140-6736(14)61730-X | pmc=4608367}}</ref>
<ref name = "Neesse_2016">{{cite journal | vauthors = Neesse A, Ellenrieder V | title = NEMO-CXCL12/CXCR4 axis: a novel vantage point for antifibrotic therapies in chronic pancreatitis? | journal = Gut | volume = 66 | issue = 2 | date = September 2016 | pmid = 27590996 | doi = 10.1136/gutjnl-2016-312874 | pages=gutjnl–2016–312874| s2cid = 3493909 }}</ref>
<ref name="Oberlin_1996">{{cite journal | vauthors = Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, Schwartz O, Heard JM, Clark-Lewis I, Legler DF, Loetscher M, Baggiolini M, Moser B | title = The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1 | journal = Nature | volume = 382 | issue = 6594 | pages = 833–5 | year = 1996 | pmid = 8752281 | doi = 10.1038/382833a0 | bibcode = 1996Natur.382..833O | s2cid = 4233446 | url = https://kops.uni-konstanz.de/bitstream/123456789/37569/1/Oberlin_0-367196.pdf }}</ref>
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<ref name = "Sorrentino_2016">{{cite journal | vauthors = Sorrentino C, Miele L, Porta A, Pinto A, Morello S | title = Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression | journal = Oncotarget | volume = 7 | issue = 39 | pages = 64274–64288 | date = August 2016 | pmid = 27590504 | pmc = 5325441 | doi = 10.18632/oncotarget.11729 }}</ref>
<ref name="Takano_2014">{{cite journal | vauthors = Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, Uehara N, Nomiyama H, Koyano K, Kukita T | title = Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis | journal = Laboratory Investigation | volume = 94 | issue = 3 | pages = 286–96 | year = 2014 | pmid = 24395111 | doi = 10.1038/labinvest.2013.152 | doi-access = free }}</ref>
<ref name="Zheng_2007">{{cite journal | vauthors = Zheng H, Fu G, Dai T, Huang H | title = Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway | journal = Journal of Cardiovascular Pharmacology | volume = 50 | issue = 3 | pages = 274–80 | year = 2007 | pmid = 17878755 | doi = 10.1097/FJC.0b013e318093ec8f | s2cid = 13616442 | doi-access = free }}</ref>
}}
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ | title = Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis | journal = Stem Cells | volume = 23 | issue = 7 | pages = 879–94 | date = August 2005 | pmid = 15888687 | doi = 10.1634/stemcells.2004-0342 | s2cid = 22504846 | doi-access =  }}
* {{cite journal | vauthors = Kryczek I, Wei S, Keller E, Liu R, Zou W | title = Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis | journal = American Journal of Physiology. Cell Physiology | volume = 292 | issue = 3 | pages = C987–95 | date = March 2007 | pmid = 16943240 | doi = 10.1152/ajpcell.00406.2006 | s2cid = 7423893 | url = https://semanticscholar.org/paper/99e7e543c00165223a7b92af16573f43e1b69e84 }}
* {{cite journal | vauthors = Stellos K, Gawaz M | title = Platelets and stromal cell-derived factor-1 in progenitor cell recruitment | journal = Seminars in Thrombosis and Hemostasis | volume = 33 | issue = 2 | pages = 159–64 | date = March 2007 | pmid = 17340464 | doi = 10.1055/s-2007-969029 | s2cid = 260320898 }}
* {{cite journal | vauthors = Wang J, Liu X, Lu H, Jiang C, Cui X, Yu L, Fu X, Li Q, Wang J | title = CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice | journal = Brain, Behavior, and Immunity | volume = 45 | pages = 98–108 | date = March 2015 | pmid = 25526817 | pmc = 4342301 | doi = 10.1016/j.bbi.2014.12.015 }}
* {{cite journal | vauthors = Arya M, Ahmed H, Silhi N, Williamson M, Patel HR | title = Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration | journal = Tumour Biology | volume = 28 | issue = 3 | pages = 123–31 | year = 2007 | pmid = 17510563 | doi = 10.1159/000102979 | s2cid = 44356923 }}
{{refend}}
{{PDB Gallery|geneid=6387}}
{{Chemokines}}
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[[Category:Cytokines]]