Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05109 (S100A8)
 1,212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S100A12 is a member of the S100 family of EF-hand calcium-binding proteins. Together with two other calgranulins, S100A8 and S100A9, it is mostly expressed in human granulocytes, although there is increasing evidence of expression in keratinocytes and psoriatic lesions. It is involved in host-parasite response, and linked to corneal autoimmune diseases connected with filarial parasite infestation. Interaction of S100A12 with a multiligand receptor for advanced glycation end products (RAGE) mediates inflammation. Human recombinant S100A12 was found to induce neuritogenesis of cultured hippocampal cells, similar to two other S100 proteins, S100B and S100A4. X-ray structure of S100A12 has been solved in two crystal forms: R3 and P2(1). In the R3 crystal form S100A12 is a dimer, and in the P2(1) crystal form the dimers are arranged as a hexamer. The hexameric form suggests its role in receptor oligomerisation. S100A12 binds copper at the predicted zinc/copper binding site, which is located close to the surface of the protein. We propose copper-mediated generation of reactive oxygen species by S100A12 as its function in host-parasite response.
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PMID:Multiple structural states of S100A12: A key to its functional diversity. 1264 6

Three members of the S100 family of calcium-binding proteins comprise a new group of proinflammatory molecules released by phagocytes. A novel inflammatory syndrome defined by extraordinarily high expression of S100A8 and S100A9 confirmed recent observations in vitro demonstrating a role of these proteins during recruitment of leukocytes. S100A12 directly activates endothelial cells, mononuclear phagocytes and lymphocytes through interaction with the receptor for advanced glycation end products. Thus, these S100-proteins are attractive targets to modulate inflammation.
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PMID:Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. 1269 38

S100 proteins are calcium-activated signaling proteins that interact with target proteins to modulate biological processes. Our present studies compare the level of expression, and cellular localization of S100A7, S100A8, S100A9, S100A10, and S100A11 in normal and psoriatic epidermis. S100A7 and S100A11 are present in the basal and spinous layers in normal epidermis. These proteins appear in the nucleus and cytoplasm in basal cells but are associated with the plasma membrane in spinous cells. S100A10 is present in basal and spinous cells, in the cytoplasm, and is associated with the plasma membrane. S100A8 and S100A9 are absent or are expressed at minimal levels in normal epidermis. In involved psoriatic tissue, S100A10 and S100A11 levels remain unchanged, whereas, S100A7, S100A8, and S100A9 are markedly overexpressed. The pattern of expression and subcellular localization of S100A7 is similar in normal and psoriatic tissue. S100A8 and S100A9 are strongly expressed in the basal and spinous layers in psoriasis-involved tissue. In addition, we demonstrate that S100A7, S100A10, and S100A11 are incorporated into detergent and reducing agent-resistant multimers, suggesting that they are in vivo transglutaminase substrates. S100A8 and S100A9 did not form these larger complexes. These results indicate that S100 proteins localize to the plasma membrane in differentiated keratinocytes, suggesting a role in regulating calcium-dependent, membrane-associated events. These studies also indicate, as reported previously, that S100A7, S100A8, and S100A9 expression is markedly altered in psoriasis, suggesting a role for these proteins in disease pathogenesis.
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PMID:S100 protein subcellular localization during epidermal differentiation and psoriasis. 1270 15

S100A12 is a member of the S100 family of EF-hand calcium-modulated proteins. Together with S100A8 and S100A9, it belongs to the calgranulin subfamily, i.e. it is mainly expressed in granulocytes, although there is an increasing body of evidence of expression in keratinocytes and psoriatic lesions. As well as being linked to inflammation, allergy and neuritogenesis, S100A12 is involved in host-parasite response, as are the other two calgranulins. Recent data suggest that the function of the S100-family proteins is modulated not only by calcium, but also by other metals such as zinc and copper. Previously, the structure of human S100A12 in low-calcium and high-calcium structural forms, crystallized in space groups R3 and P2(1), respectively, has been reported. Here, the structure of S100A12 in complex with copper (space group P2(1)2(1)2; unit-cell parameters a = 70.6, b = 119.0, c = 90.2 A) refined at 2.19 A resolution is reported. Comparison of anomalous difference electron-density maps calculated with data collected with radiation of wavelengths 1.37 and 1.65 A shows that each monomer binds a single copper ion. The copper binds at an equivalent site to that at which another S100 protein, S100A7, binds zinc. The results suggest that copper binding may be essential for the functional role of S100A12 and probably the other calgranulins in the early immune response.
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PMID:Structure of the human S100A12-copper complex: implications for host-parasite defence. 1277 2

Recently, proinflammatory activities had been described for S100A8 and S100A9, two proteins found at inflammatory sites and within the neutrophil cytoplasm. In this study, we investigated the role of these proteins in neutrophil migration in vivo in response to LPS. LPS was injected into the murine air pouch, which led to the release of S100A8, S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation of neutrophils. Passive immunization against S100A8 and S100A9 led to a 52% inhibition of neutrophil migration in response to LPS at 3 h postinjection. Injection of LPS was also associated with an increase in peripheral blood neutrophils and the presence in serum of S100A9 and S100A8/A9. Intravenous injection of S100A8, S100A9, or S100A8/A9 augmented the number of circulating neutrophils and diminished the number of neutrophils in the bone marrow, demonstrating that S100A8 and S100A9 induced the mobilization of neutrophils from the bone marrow to the blood. Finally, passive immunization with anti-S100A9 inhibited the neutrophilia associated with LPS injection in the air pouch. These results suggest that S100A8 and S100A9 play a role in the inflammatory response to LPS by inducing the release of neutrophils from the bone marrow and directing their migration to the inflammatory site.
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PMID:Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide. 1463 68

Ovarian cancer remains still associated with poor prognosis because it is diagnosed predominantly at advanced stages. Ovarian-specific tumor markers do not yet exist for early detection of the disease. At the search of diagnostic markers for ovarian cancer, proteomic-based approaches have focused on novel investigations of neoplastic processes in tumor patients. Cystic fluids of malignant and benign ovarian tumors and serum from the corresponding patients were collected and processed for two-dimensional gel electrophoresis. Proteins were visualized on the gels by silver staining. At the low molecular mass level between 10 and 20 kDa, selected protein spots were additionally processed for nanospray mass spectrometry and partial amino acid sequencing. For protein identification, the sequencing results were compared with computer information from a protein data bank. Protein patterns from cystic fluids of ovarian carcinomas differed significantly from those of benign cysts and revealed additional polypeptides at low molecular mass level between 10 and 20 kDa. Protein patterns from serum of patients with malignant ovarian tumors also contained additional polypeptides between 10 and 20 kDa that were not detected in serum from patients with benign cysts. The additional proteins in serum were present in similar electrophoretic positions compared with those found in the cystic fluid of the corresponding ovarian carcinomas. Protein spots in the range of 10-20 kDa were selected for partial amino acid sequencing. Two protein spots were identified as calgranulin A and three spots as calgranulin B. Either both proteins or only calgranulin A or B were present in cystic fluid from ovarian carcinomas and serum of the corresponding patients. These two proteins were absent or not detectable in fluid from benign ovarian cysts and in serum from those patients. Our investigations concerning protein patterns in cystic fluid of malignant and benign ovarian tumors provide new information about alterations in protein synthesis linked to neoplastic events of the ovary. With the proteomic strategy, new tumor markers are characterized and may serve for diagnostic purposes of patients with ovarian cancer.
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PMID:Calgranulins in cystic fluid and serum from patients with ovarian carcinomas. 1461 52

To identify genes that are differentially expressed in human esophageal squamous cell carcinoma (ESCC), we have developed a cDNA microarray representing 34 176 clones to analyse gene expression profiles in ESCC. A total of 77 genes (including 31 novel genes) were downregulated, and 15 genes (including one novel gene) were upregulated in cancer tissues compared with their normal counterparts. Immunohistochemistry and Northern blot analysis were carried out to verify the cDNA microarray results. It was revealed that genes involved in squamous cell differentiation were coordinately downregulated, including annexin I, small proline-rich proteins (SPRRs), calcium-binding S100 proteins (S100A8, S100A9), transglutaminase (TGM3), cytokeratins (KRT4, KRT13), gut-enriched Krupple-like factor (GKLF) and cystatin A. Interestingly, most of the downregulated genes encoded Ca(2+)-binding or -modulating proteins that constitute the cell envelope (CE). Moreover, genes associated with invasion or proliferation were upregulated, including genes such as fibronectin, secreted protein acidic and rich in cystein (SPARC), cathepsin B and KRT17. Functional analysis of the alteration in the expression of GKLF suggested that GKLF might be able to regulate the expression of SPRR1A, SPRR2A and KRT4 in ESCC. This study provides new insights into the role of squamous cell differentiation-associated genes in ESCC initiation and progression.
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PMID:Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray. 1464 9

Cutaneous exposure to ultraviolet (UV) A (320-400 nm) results in the formation of damaging reactive oxygen intermediates, which are implicated as mediators of DNA damage, apoptosis, and photoaging. S100A8 is a low-molecular-weight calcium-binding protein, highly sensitive to oxidation. In this study, UVA-induced S100A8 expression by keratinocytes was investigated. UVA (50-100 kJ per m2) strongly induced S100A8 in differentiated keratinocytes in the epidermis of BALB/c mice. Similarly, S100A8 mRNA and monomeric protein were significantly upregulated in PAM212 cells (a murine keratinocyte cell line) in response to 10 kJ per m2 UVA 24 h after irradiation. Although S100A9 associates with S100A8 in neutrophils and abnormally differentiated keratinocytes (human psoriasis), in this study it was not coinduced with keratinocyte S100A8. Dorsal application of 4-hydroxy-tempo (a superoxide dismutase-mimicking agent) to mice concentration-dependently reduced UVA-induced S100A8 expression. Incubation of PAM212 cells with superoxide dismutase and catalase during UVA irradiation also abrogated S100A8 induction. These results suggest that UVA-induced S100A8 is expressed by keratinocytes in response to generation of reactive oxygen intermediates.
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PMID:S100A8 induction in keratinocytes by ultraviolet A irradiation is dependent on reactive oxygen intermediates. 1470 22

During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity. Even if their role as activators of the host immune response has been studied, the direct contribution of hemozoin (HZ), a parasite metabolite, to such a strong induction is not fully understood. Previous in vitro studies demonstrated that both Plasmodium falciparum HZ and synthetic HZ (sHZ), beta-hematin, induce macrophage/monocyte chemokine and proinflammatory cytokine secretion. In the present study, we investigated the proinflammatory properties of sHZ in vivo. To this end, increasing doses of sHZ were injected either i.v. or into an air pouch generated on the dorsum of BALB/c mice over a 24-h period. Our results showed that sHZ is a strong modulator of leukocyte recruitment and more specifically of neutrophil and monocyte populations. In addition, evaluation of chemokine and cytokine mRNA and protein expression revealed that sHZ induces the expression of chemokines, macrophage-inflammatory protein (MIP)-1alpha/CCL3, MIP-1beta/CCL4, MIP-2/CXCL2, and monocyte chemoattractant protein-1/CCL2; chemokine receptors, CCR1, CCR2, CCR5, CXCR2, and CXCR4; cytokines, IL-1beta and IL-6; and myeloid-related proteins, S100A8, S100A9, and S100A8/A9, in the air pouch exudates. Of interest, chemokine and cytokine mRNA up-regulation were also detected in the liver of i.v. sHZ-injected mice. In conclusion, our study demonstrates that sHZ is a potent proinflammatory agent in vivo, which could contribute to the immunopathology related to malaria.
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PMID:Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection. 1497 16

Macrophages are decisive cells for the course of leprosy as they phagocytose Mycobacterium leprae and have the potential to influence the specific immune response. Expression and release of the myeloid-related protein (MRP) 8 and MRP14 (S100A8 and S100A9) characterize a proinflammatory subtype of macrophage that is prominent in, for example, murine infection with lack of a T helper 1 cell response and in certain highly active chronic inflammations of mice and humans. We investigated cutaneous biopsies of the different forms of leprosy (41 untreated patients) including leprosy reaction type 1 (reversal reaction) and type 2 (erythema nodosum leprosum) (n = 18) for expression of MRP8 and MRP14 by subtypes of macrophages. Concomitantly we determined serum levels of MRP8 and MRP14 by sandwich enzyme-linked immunosorbent assay. Expression of MRP8 and MRP14 by CD68-positive macrophages was low in tuberculoid leprosy and rose significantly in borderline tuberculoid leprosy and especially in multibacillary forms, there being expressed by mycobacteria-loaded foam cells. A significant rise of MRP8 and MRP14 expression also occurred in lepra reactions compared to the corresponding non-reactional forms. In type 2 reactions this additional increase was associated with a significant elevation of serum levels. In type 1 it was associated with expression of MRP8 and MRP14 by epitheloid and giant cells, which so far were considered not to express both proteins. In conclusion, we present evidence that the two prominent proteins MRP8 and MRP14 can be re-expressed in vivo by tissue macrophages in chronic infection, that their increased expression is characteristic for a macrophage subtype associated with high inflammatory but low antimycobacterial activity in the absence of a T helper 1 response, and that their significant rise in serum during erythema nodosum leprosum bears diagnostic and pathophysiological relevance.
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PMID:High expression of myeloid-related proteins 8 and 14 characterizes an inflammatorily active but ineffective response of macrophages during leprosy. 1505 85


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