Disease relevance of S100A7

• Psoriasin (S100A7) is expressed at low levels in normal breast epithelial cells but is highly expressed in preinvasive ductal carcinoma in situ [1].
• Using differential screening of a breast cancer cDNA library, we isolated a cDNA encoding the psoriasin (S100A7) protein, previously identified in psoriatic epidermis [2].
• S100A7 and S100A9 have been shown to be markedly upregulated both in ductal carcinoma in situ of the breast and in psoriasis [3].
• The protein co-migrated with psoriasin as determined by two-dimensional (2D) gel analysis of [35S]-methionine-labeled proteins expressed by RK13 cells transfected with clone 1085 using the vaccinia virus expression system [4].
• For example, S100A7 is upregulated in psoriatic skin, implicating a link with psoriasis, a chronic inflammatory dermatosis [5].

High impact information on S100A7

• Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction [6].
• Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism [6].
• Finally, we show that psoriasin expression is induced by the topoisomerase IIalpha poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent [7].
• Furthermore, the Jab1-binding domain is also necessary for the enhanced tumorigenicity conferred by S100A7 expression in murine xenograft tumors in vivo [8].
• BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene [7].

Chemical compound and disease context of S100A7

• A recent report by Schröder and colleagues suggests that psoriasin, purified from human stratum corneum extracts, selectively kills Escherichia coli by sequestering Zn(2+) ions essential for bacterial growth, indicative of an important role in innate immune defense against microbial infection [9].
• Here we have used the psoriasin cDNA to express recombinant human (rh) psoriasin in Escherichia coli as a fusion protein containing a hexa His tag and a factor Xa cleavage site in the NH2-terminus [10].
• Topical all-trans retinoic acid (RA) induces an early, coordinated increase in RA-inducible skin-specific gene/psoriasin and cellular RA-binding protein II mRNA levels which precedes skin erythema [11].

Biological context of S100A7

• Comparative expression of the psoriasin (S100A7) and S100C genes in breast carcinoma and co-localization to human chromosome 1q21-q22 [2].
• This is the first report of five copies of the S100A7 gene in the human genome, which may impact on our understanding of the possible dose effects of these genes in inflammation and normal skin development and pathogenesis [12].
• Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development [13].
• Analysis of the deduced amino acid sequence revealed a protein of 101 amino acids containing two potential EF-hand motifs with high homology to the S100A7 [14].
• To explore the mechanism of action, we examined the role of S100A7 in cell survival and found that overexpression of S100A7 in MDA-MB-231 cell lines promotes survival under conditions of anchorage-independent growth [8].

Anatomical context of S100A7

• Increased expression of psoriasin mRNA in psoriatic keratinocytes was confirmed by Northern blotting and in situ hybridization [4].
• Psoriasin was not detected in normal human fibroblasts, lymphocytes, endothelial cells and transformed epithelial cells of keratinocyte origin [4].
• We show that S100A7 is present in the cytosol and in BiP/GRP78-positive (endoplasmic reticulum) tubular structures [15].
• These data indicate that E-FABP and S100A7 might form a complex in the cytosol of human keratinocytes [16].
• S100A7 was mapped physically by human/rodent somatic cell hybrid analysis, and more precisely genetically by multilocus linkage analysis of 40 CEPH (Centre d'Etude du Polymorphisme Humain) families [17].

Associations of S100A7 with chemical compounds

• Using purified E-FABP and S100A7, the complex can be reconstituted only in presence of EDTA [18].
• RESULTS: The three-dimensional structure of holmium-substituted psoriasin has been determined by multiple anomalous wavelength dispersion (MAD) phasing and refined to atomic resolution (1.05 A) [19].
• cDNA cloning and protein analysis of a bovine dermal allergen with homology to psoriasin [20].
• Of these, psoriasin, the psoriasis-associated fatty acid binding protein 5, the gelsolin fragments and prostaglandin D2 synthetase have not been previously described [21].
• Finally, several markers of keratinocyte activation such as the integrin chain alpha(v), psoriasin, glutathion-S-transferase and heparin-binding epidermal growth factor-like growth factor were up-regulated [22].

Physical interactions of S100A7

• E-FABP interacts with S100A7 [23].
• In addition, S100A7 expression appears to stabilize epidermal fatty acid binding protein level, and vice versa [15].
• RanBPM interacts with psoriasin in vitro and their expression correlates with specific clinical features in vivo in breast cancer [24].
• The polypeptide sequence derived from the partial RIS-1 cDNA was found to be identical to the calcium binding domain found in 'psoriasin', a gene whose expression appears to be increased in the skin of psoriasis patients [25].

Regulatory relationships of S100A7

• Furthermore, we demonstrate that overexpression of a dominant negative IKKbeta also inhibits the induction of psoriasin suggesting that the NFkappaB pathway is involved in the induction of this protein [26].
• Correlating with this, high psoriasin expression in human IBC is associated with increased angiogenesis and worse clinical outcome, and psoriasin mRNA levels are coordinately regulated with VEGF and other genes related to hypoxia and mitochondrial reactive oxygen species (ROS) [27].
• RanBPM mRNA is also frequently expressed in invasive breast carcinomas (n = 64) and a higher psoriasin/RanBPM ratio is associated with both ER negative (p < 0.0001) and PR negative status (p < 0.001), and inflammatory cell infiltrates (p < 0.0001) within the tumor [24].

Other interactions of S100A7

• S100A7 and S100A11 are present in the basal and spinous layers in normal epidermis [28].
• We used PCR to amplify an indel within intron 1 of the S100A7a and S100A7c genes that gave the same two expected product sizes using 40 human DNA samples and 1 chimpanzee sample, therefore confirming the presence of the region 1 and 3 duplication in these species [12].
• Using S100A10 as new bait, a specific interaction with S100A7 was detectable [29].
• We conclude that the S100A7-Jab1 pathway acts to enhance survival under conditions of cellular stress, such as anoikis, which may promote progression of breast cancer [8].
• These data indicate that formation of the E-FABP-S100A7 complex and its FA-binding function might be regulated at least by bivalent cations [18].

Analytical, diagnostic and therapeutic context of S100A7

• Molecular cloning, occurrence, and expression of a novel partially secreted protein "psoriasin" that is highly up-regulated in psoriatic skin [4].
• Psoriasin showed a restricted occurrence in fetal human tissues as determined by 2D gel electrophoresis [4].
• By using confocal microscopy we show that S100A7 and E-FABP are co-localized in the cytoplasm of differentiating keratinocytes from lesional psoriatic skin [18].
• Gel filtration and non-denaturing PAGE revealed that S100A7 co-purified with E-FABP, indicating an association between the two proteins [16].
• By SDS-PAGE immunoblotting we show that E-FABP and S100A7 are expressed in cultured human differentiating keratinocytes and confirm their overexpression in psoriatic scales [16].

References