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)

Calcium-binding S100 proteins are thought to play a central role in calcium-mediated signal transduction pathways. They consist of two helix-loop-helix, calcium-binding EF-hand domains. A characteristic feature is their tendency to form homo- and/or heterodimeric complexes. This report presents for the first time a functional "in vivo" approach to the analysis of S100 protein dimerization. Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse. The ability to homodimerize, however, appears to be restricted to the murine MRPs. Interaction analysis of chimeric murine/human MRP14 proteins indicates, that the C-terminal EF-hand domain plays a prominent role in MRP8-MRP14 interaction and determines the specificity of dimerization. Site-directed mutagenesis of four evolutionary conserved hydrophobic amino acids, which have been recently supposed to be essential for S100 protein dimerization, suggests that at least one of these, namely the most N-terminal located residue, is not critical for dimerization.
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PMID:Analysis of the MRP8-MRP14 protein-protein interaction by the two-hybrid system suggests a prominent role of the C-terminal domain of S100 proteins in dimer formation. 986 28

The two migration inhibitory factor- (MIF)-related protein-8 (MRP8; S100A8) and MRP14 (S100A9) are two calcium-binding proteins of the S100 family. These proteins are expressed during myeloid differentiation, are abundant in granulocytes and monocytes, and form a heterodimeric complex in a Ca2+-dependent manner. Phagocytes expressing MRP8 and MRP14 belong to the early infiltrating cells and dominate acute inflammatory lesions. In addition, elevated serum levels of MRP8 and MRP14 have been found in patients suffering from a number of inflammatory disorders including cystic fibrosis, rheumatoid arthritis, and chronic bronchitis, suggesting conceivable extracellular roles for these proteins. Although a number of possible functions for MRP8/14 have been proposed, the biological function still remains unclear. This review addresses recent developments regarding the MRP14-mediated promotion of leukocyte-endothelial cell-interactions and the characterization of MRP8/14 heterodimers as a fatty acid binding protein complex. In view of the current knowledge, the authors will hypothesize that MRP8 and MRP14 play an important role in leukocyte trafficking, but do not affect neutrophil effector functions.
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PMID:Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9). 992 Apr 11

S100 Ca2+-binding proteins became of major interest because of their differential expression in tissues and their association with human diseases. Earlier studies showed that 13 S100 genes are located as a cluster on human chromosome 1q21. Since a number of mouse S 100 genes, such as S100A4 and S100A6, have been localized to a syntenic region on mouse chromosome 3, we investigated if the S100 gene cluster exists in mouse and is structurally conserved during evolution. First we identified the cDNA sequences of mouse S100A1, S100A3 and S100A5. Then we isolated a 490 kb mouse YAC clone which gives a specific signal by FISH most likely on chromosome 3. Hybridization studies with different mouse S100 cDNAs revealed that eight mouse S100 genes are arranged in a clustered organization similar to that in human. The linkage relationships between the genes S100A8-S100A9 and S100A3-S100A4-S100A5-S100A6 were conserved during divergence of human and mouse about 70 million years ago. However, the separation of the mouse S100 genes S100A1 and S100A13 in comparison to the human linkage group suggests rearrangement processes between human and mouse. Our data demonstrate that the S100 gene cluster is structurally conserved during evolution. Further studies on the genomic organization of the S100 genes including various species could generate new insights into gene regulatory processes and phylogenetic relationships.
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PMID:Clustered organization of S100 genes in human and mouse. 992 Apr 16

A panel of 6 human glioma cell lines was examined for TGF-beta1 responsiveness. U-178 MG and U-251 MG AgCl1 were significantly inhibited by TGF-beta1, while U-343 MGa 31L and U-343 MGa 35L were potently stimulated to proliferate. TGF-beta1 induced endogenous PAI-1 protein synthesis, Smad binding element/(CAGA)12-luciferase-reporter activity, as well as mRNA expression of Smad6 and Smad7 in all gliomas. Interestingly, TGF-beta1 differentially stimulated or inhibited the expression of TbetaR-I and TbetaR-II mRNA in the gliomas. Affinity cross-linking studies using 125I-TGF-beta1 revealed that the gliomas expressed TGF-beta-type-I(TbetaR-I) and -type-II(TbetaR-II) receptors, although binding to TbetaR-II in U-343 MGa 31L and U-251 MG AgCl1 was low to undetectable. Smad2 protein was abundantly present in U-178 MG, U-343 MG, and U-343 MGa 35L, while Smad3 was readily detectable in U-178 MG, U-343 MG, U-343 MGa 35L and U-251 MG AgCl1. In all gliomas, TGF-beta1 induced phosphorylation of Smad2. The level to which TGF-beta1 could activate the pathway leading to induction of the (CAGA)12-luciferase reporter seemed to correlate to the expression levels of TGF-beta receptors, Smad3 and Smad4 proteins. However, despite the plethora of data regarding TGF-beta1 signalling in the different glioma cell lines, the mechanism underlying the differential growth effects mediated by TGF-beta1 is still unclear. The results suggest that a complex balance between several components in the TGF-beta signalling pathway controls glioma responsiveness to TGF-beta1, and extend reports indicating that distinct signal transduction pathways are involved in growth inhibition and other cellular responses.
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PMID:Expression of transforming-growth-factor (TGF)-beta receptors and Smad proteins in glioblastoma cell lines with distinct responses to TGF-beta1. 1004 79

Chronic inflammatory discoid lupus erythematosus (DLE) and Jessner's lymphocytic infiltration of the skin (LIS) are both characterized by dermal infiltrates of activated T lymphocytes. However, an inflammatory involvement of the epidermis is only found in DLE. We therefore compared the phenotypic properties of the keratinocytes using immunohistochemical stainings of biopsies from typical DLE and LIS. Keratinocytes failed to express HLA-DR in LIS and surprisingly also in DLE. The adhesion molecule ICAM-1 was only expressed in DLE, with focal staining of the basal keratinocytes in close association with intraepidermal lymphocytes. The monoclonal antibody 27E10, a distinct marker for macrophage activation and differentiation, revealed a strong band-like labelling of the suprabasal and upper keratinocytes in DLE. In contrast, no epidermal expression of this biologically active heterodimer of the calcium-binding proteins MRP-8 and MRP-14 was found in LIS. The staining patterns provide a new method to differentiate DLE and LIS by immunohistochemistry and suggest a distinct type of keratinocyte activation and differentiation in DLE which would in turn mediate epidermal T cell infiltration.
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PMID:Macrophage marker 27E10 on human keratinocytes helps to differentiate discoid lupus erythematosus and Jessner's lymphocytic infiltration of the skin. 1006 57

The myeloid cell-derived calcium-binding murine protein, S100A8, is secreted to act as a chemotactic factor at picomolar concentrations, stimulating recruitment of myeloid cells to inflammatory sites. S100A8 may be exposed to oxygen metabolites, particularly hypochlorite, the major oxidant generated by activated neutrophils at inflammatory sites. Here we show that hypochlorite oxidizes the single Cys residue (Cys41) of S100A8. Electrospray mass spectrometry and SDS-polyacrylamide gel electrophoresis analysis indicated that low concentrations of hypochlorite (40 microM) converted 70-80% of S100A8 to the disulfide-linked homodimer. The mass was 20,707 Da, 92 Da more than expected, indicating additional oxidation of susceptible amino acids (possibly methionine). Phorbol 12-myristate 13-acetate activation of differentiated HL-60 granulocytic cells generated an oxidative burst that was sufficient to efficiently oxidize exogenous S100A8 within 10 min, and results implicate involvement of the myeloperoxidase system. Moreover, disulfide-linked dimer was identified in lung lavage fluid of mice with endotoxin-induced pulmonary injury. S100A8 dimer was inactive in chemotaxis and failed to recruit leukocytes in vivo. Positive chemotactic activity of recombinant Ala41S100A8 indicated that Cys41 was not essential for function and suggested that covalent dimerization may structurally modify accessibility of the chemotactic hinge domain. Disulfide-dependent dimerization may be a physiologically significant regulatory mechanism controlling S100A8-provoked leukocyte recruitment.
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PMID:Oxidation regulates the inflammatory properties of the murine S100 protein S100A8. 1008 90

Smad proteins are essential components of the signalling cascade initiated by members of the Transforming Growth Factor-beta family. TGFbeta binding to heteromeric complexes of transmembrane Ser/Thr kinases induces Smad2 and Smad3 phosphorylation on their C terminus residues. This phosphorylation leads to oligomerization with Smad4, a common mediator of TGF-beta, activin and BMP signalling. The Smad complexes then translocate to the nucleus where they play transcription regulator roles. Even if they share 92% identity, the two TGFbeta/ restricted Smad2 and Smad3 are not functionally equivalent. As we have previously shown, Smad3 acts as a transcription factor by binding to a TGFbeta-responsive sequence termed CAGA box whereas Smad2 does not. Smad2 differs from Smad3 mainly in the N-terminal MH1 domain where it contains two additional stretches of amino acids that are lacking in Smad3. Here, we show that one of these domains corresponding to exon 3 is responsible for the absence of Smad2 transcriptional activity in CAGA box-containing promoters. Furthermore, in vitro studies indicate that this domain prevents Smad2 from binding to this DNA sequence. This suggests that Smad2 and Smad3 may have different subsets of target genes participating thus in distinct responses among TGFbeta pleiotropic effects.
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PMID:A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. 1010 36

Proteins secreted by epidermal keratinocytes are known to engage in functions other than those directly associated with barrier formation. We have used a previously published culture model to collect proteins secreted by adult human epidermal keratinocytes. Electrophoresis and microsequencing allowed us to identify 20 proteins. The list of proteins includes those known to be produced by keratinocytes (beta-2 microglobulin, betaIG-H3, calgranulin A, cathepsin B and D, E-cadherin, gelatinase B, gelsolin, interstitial collagenase, laminin B2t, plasminogen activator inhibitor-1, protein 14-3-3epsilon, SCC antigen, stratifin, and translationally controlled tumor protein) as well as those not previously known to be secreted by keratinocytes (epididymis secretory protein, maspin, and anti-neoplastic urinary protein). In addition, two proteins were identified that are not known to be secreted (glutathione-S-transferase and heat shock protein 27/28 kDa). The varied nature of the proteins identified suggests that epidermal keratinocytes have physiologic functions that have yet to be identified.
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PMID:A partial catalog of proteins secreted by epidermal keratinocytes in culture. 1023 78

Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.
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PMID:Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes. 1031 95

The expression of calcium-binding protein S100A9 was investigated in 23 matched sets of colorectal carcinoma and normal colon mucosa using two-dimensional gel electrophoresis. We found that, from a group of 23 patients, the level of S100A9 protein, in comparison with matched normal colon mucosa, was significantly increased in malignant tissues of 16 patients (70%). Furthermore, an additional protein, identified by matrix-assisted laser desorption/ionization - mass spectrometry (MALDI-MS) as S100A8, exhibited an increased expression in the same specimens of malignant tissues as the S100A9 protein. The immunohistological analysis revealed the accumulation of S100A9 positive cells, macrophages and polymorphonuclear leukocytes along the invasive margin of colorectal carcinoma. The S100A8 protein was found to be produced in the same location. The possible participation of both proteins and, especially, its heterodimeric complex calprotectin in colorectal carcinoma regression could be taken into account.
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PMID:The analysis of S100A9 and S100A8 expression in matched sets of macroscopically normal colon mucosa and colorectal carcinoma: the S100A9 and S100A8 positive cells underlie and invade tumor mass. 1034 84


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