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S100A9

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Template:PBB S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene.[1]

The proteins S100A8 and S100A9 form a heterodimer called calprotectin.

Function

S100-A9 is a member of the S100 family of proteins containing 2 EF hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition of casein kinase.[1]

MRP14 complexes with MRP-8 (S100A8), another member of the S100 family of calcium-modulated proteins; together, MRP8 and MRP14 regulate myeloid cell function by binding to Toll-like receptor 4 (TLR4)[2] and the receptor for advanced glycation end products.[3]

Clinical significance

Altered expression of the S100A9 protein is associated with the disease cystic fibrosis.[1]

MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.[4]

MRP-8/14 also regulates vascular insults by controlling neutrophil and macrophage accumulation, macrophage cytokine production, and SMC proliferation. The above study has shown therefore the deficiency of MRP-8 and MRP-14 reduces neutrophil- and monocyte-dependent vascular inflammation and attenuates the severity of diverse vascular injury responses in vivo. MRP-8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.[5] Also, the platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before ST-segment-elevation myocardial infarction, (STEMI), and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.[6]

S100A9 (myeloid-related protein 14, MRP 14 or calgranulin B) has been implicated in the abnormal differentiation of myeloid cells in the stroma of cancer.[7] This contributes to creating an overall immunosuppressive microenvironment that may contribute to the inability of a protective or therapeutic cellular immune response to be generated by the tumor-bearing host. Outside of malignancy, S100A9 in association with its dimerization partner, S100A8 (MRP8 or calgranulin A) signals for lymphocyte recruitment in sites of inflammation.[8] S100A9/A8 (synonyma: Calgranulin A/B; Calprotectin) are also regarded as marker proteins for a number of inflammatory diseases in humans, especially in rheumatoid arthritis.

Myeloid-related protein (MRP)-8 is an inflammatory protein found in several mucosal secretions. In cervico-vaginal secretions MRP-8 can stimulate HIV production;[9] and thus might be involved in sexual transmission of HIV, as well as other sexually transmitted diseases (STD). In Vitro studies have shown that HIV-inducing of recombinant MRP-8 can increase HIV expression by up to 40-fold.[10]

Animal studies

A S100A9 knockout mouse has (a mouse mutant, that is deficient of S100A9) been constructed. This mouse is fertile, viable and healthy. However, expression of S100A8 protein, the dimerization partner of S100A9, is also absent in these mice in differentiated myeloid cells.[11] This mouse line has been used to study the role of S100A9 and S100A8 in a number of experimental inflammatory conditions.

See also

References

  1. ^ a b c "Entrez Gene: S100A9 S100 calcium binding protein A9".
  2. ^ Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (September 2007). "Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock". Nat. Med. 13 (9): 1042–9. doi:10.1038/nm1638. PMID 17767165.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Boyd JH, Kan B, Roberts H, Wang Y, Walley KR (May 2008). "S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products". Circ. Res. 102 (10): 1239–46. doi:10.1161/CIRCRESAHA.107.167544. PMID 18403730.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Croce K, Gao H, Wang Y, Mooroka T, Sakuma M, Shi C, Sukhova GK, Packard RR, Hogg N, Libby P, Simon DI (August 2009). "MRP-8/14 is Critical for the Biological Response to Vascular Injury". Circulation. 120 (5): 427–36. doi:10.1161/CIRCULATIONAHA.108.814582. PMC 3070397. PMID 19620505.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Morrow DA, Wang Y, Croce K, Sakuma M, Sabatine MS, Gao H, Pradhan AD, Healy AM, Buros J, McCabe CH, Libby P, Cannon CP, Braunwald E, Simon DI (January 2008). "Myeloid-Related Protein-8/14 and the Risk of Cardiovascular Death or Myocardial Infarction after an Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial". Am. Heart J. 155 (1): 49–55. doi:10.1016/j.ahj.2007.08.018. PMC 2645040. PMID 18082488.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, Sakuma M, Shi C, Zago AC, Garasic J, Damokosh AI, Dowie TL, Poisson L, Lillie J, Libby P, Ridker PM, Simon DI (May 2006). "Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events". Circulation. 113 (19): 2278–84. doi:10.1161/CIRCULATIONAHA.105.607333. PMID 16682612.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI (September 2008). "Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein". J. Exp. Med. 205 (10): 2235–49. doi:10.1084/jem.20080132. PMC 2556797. PMID 18809714.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Hiratsuka S, Watanabe A, Aburatani H, Maru Y (December 2006). "Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis". Nat. Cell Biol. 8 (12): 1369–75. doi:10.1038/ncb1507. PMID 17128264.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Hashemi FB, Mollenhauer J, Madsen LD, Sha BE, Nacken W, Moyer MB, Sorg C, Spear GT. AIDS (2001), "Myeloid-related protein (MRP)-8 from cervico-vaginal secretions activates HIV replication". AIDS;15(4):441-9. "PMID11242140 [PubMed - indexed for MEDLINE]">
  10. ^ Hashemi FB, Mollenhauer J, Madsen LD, Sha BE, Nacken W, Moyer MB, Sorg C, Spear GT. AIDS (2001), "Myeloid-related protein (MRP)-8 from cervico-vaginal secretions activates HIV replication". AIDS;15(4):441-9."PMID 11242140">
  11. ^ Manitz MP, Horst B, Seeliger S, Strey A, Skryabin BV, Gunzer M, Frings W, Schönlau F, Roth J, Sorg C, Nacken W (February 2003). "Loss of S100A9 (MRP14) Results in Reduced Interleukin-8-Induced CD11b Surface Expression, a Polarized Microfilament System, and Diminished Responsiveness to Chemoattractants In Vitro". Mol. Cell. Biol. 23 (3): 1034–43. doi:10.1128/MCB.23.3.1034-1043.2003. PMC 140712. PMID 12529407.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

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