1. Gene Aliases

S100A8, S100 Calcium Binding Protein A8, MRP8, P8, Migration Inhibitory Factor-Related Protein 8, Leukocyte L1 Complex Light Chain, Calprotectin L1L Subunit, Cystic Fibrosis Antigen, S100-A8, 60B8AG, MRP-8, CGLA, CAGA, CFAG, Urinary Stone Protein Band A, Protein S100-A8, Calgranulin A, S100 Calcium-Binding Protein A8, Calgranulin-A, CP-10, MA387, L1Ag, MIF, NIF [https://www.genecards.org/cgi-bin/carddisp.pl?gene=S100A8&keywords=S100a8].

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

The interactions list has been truncated to include only interactions with the strongest support from the literature.

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

GO terms:

apoptotic process [A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died. GO:0006915]

astrocyte development [The process aimed at the progression of an astrocyte over time, from initial commitment of the cell to a specific fate, to the fully functional differentiated cell. An astrocyte is the most abundant type of glial cell. Astrocytes provide support for neurons and regulate the environment in which they function. GO:0014002]

autocrine signaling [Signaling between cells of the same type. The signal produced by the signaling cell binds to a receptor on, and affects a cell of the same type. GO:0035425]

autophagy [The cellular catabolic process in which cells digest parts of their own cytoplasm; allows for both recycling of macromolecular constituents under conditions of cellular stress and remodeling the intracellular structure for cell differentiation. GO:0006914]

cellular oxidant detoxification [Any process carried out at the cellular level that reduces or removes the toxicity superoxide radicals or hydrogen peroxide. GO:0098869]

chronic inflammatory response [Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously. Although it may follow acute inflammation, chronic inflammation frequently begins insidiously, as a low-grade, smoldering, often asymptomatic response. GO:0002544]

innate immune response [Innate immune responses are defense responses mediated by germline encoded components that directly recognize components of potential pathogens. GO:0045087]

leukocyte migration involved in inflammatory response [The movement of a leukocyte within or between different tissues and organs of the body contributing to an inflammatory response. GO:0002523]

neutrophil aggregation [The adhesion of one neutrophil to one or more other neutrophils via adhesion molecules. GO:0070488]

neutrophil chemotaxis [The directed movement of a neutrophil cell, the most numerous polymorphonuclear leukocyte found in the blood, in response to an external stimulus, usually an infection or wounding. GO:0030593]

peptide secretion [The controlled release of a peptide from a cell or a tissue. GO:0002790]

positive regulation of inflammatory response [Any process that activates or increases the frequency, rate or extent of the inflammatory response. GO:0050729]

positive regulation of intrinsic apoptotic signaling pathway [Any process that activates or increases the frequency, rate or extent of intrinsic apoptotic signaling pathway. GO:2001244]

positive regulation of peptide secretion [Any process that activates or increases the frequency, rate, or extent of peptide secretion. GO:0002793]

response to ethanol [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an ethanol stimulus. GO:0045471]

response to lipopolysaccharide [Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a lipopolysaccharide stimulus; lipopolysaccharide is a major component of the cell wall of gram-negative bacteria. GO:0032496]

response to zinc ion [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a zinc ion stimulus. GO:0010043]

MSigDB Signatures:

REACTOME_ANTIMICROBIAL_PEPTIDES: Antimicrobial peptides [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ANTIMICROBIAL_PEPTIDES.html]

REACTOME_ANTIGEN_PROCESSING_CROSS_PRESENTATION: Antigen processing-Cross presentation [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ANTIGEN_PROCESSING_CROSS_PRESENTATION.html]

NABA_MATRISOME: Ensemble of genes encoding extracellular matrix and extracellular matrix-associated proteins [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_MATRISOME.html]

NABA_MATRISOME_ASSOCIATED: Ensemble of genes encoding ECM-associated proteins including ECM-affilaited proteins, ECM regulators and secreted factors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_MATRISOME_ASSOCIATED.html]

REACTOME_ADAPTIVE_IMMUNE_SYSTEM: Adaptive Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ADAPTIVE_IMMUNE_SYSTEM.html]

REACTOME_INNATE_IMMUNE_SYSTEM: Innate Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_INNATE_IMMUNE_SYSTEM.html]

REACTOME_RHO_GTPASE_EFFECTORS: RHO GTPase Effectors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_RHO_GTPASE_EFFECTORS.html]

NABA_SECRETED_FACTORS: Genes encoding secreted soluble factors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_SECRETED_FACTORS.html]

REACTOME_TOLL_LIKE_RECEPTOR_TLR1_TLR2_CASCADE: Toll Like Receptor TLR1:TLR2 Cascade [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_TOLL_LIKE_RECEPTOR_TLR1_TLR2_CASCADE.html]

REACTOME_DISEASES_OF_IMMUNE_SYSTEM: Diseases of Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_DISEASES_OF_IMMUNE_SYSTEM.html]

REACTOME_SIGNALING_BY_RHO_GTPASES_MIRO_GTPASES_AND_RHOBTB3: Signaling by Rho GTPases, Miro GTPases and RHOBTB3 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_RHO_GTPASES_MIRO_GTPASES_AND_RHOBTB3.html]

REACTOME_RHO_GTPASES_ACTIVATE_NADPH_OXIDASES: RHO GTPases Activate NADPH Oxidases [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_RHO_GTPASES_ACTIVATE_NADPH_OXIDASES.html]

REACTOME_IRAK4_DEFICIENCY_TLR2_4: IRAK4 deficiency (TLR2/4) [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_IRAK4_DEFICIENCY_TLR2_4.html]

REACTOME_NEUTROPHIL_DEGRANULATION: Neutrophil degranulation [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_NEUTROPHIL_DEGRANULATION.html]

7. Gene Descriptions

NCBI Gene Summary: The protein encoded by this gene 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 and as a cytokine. Altered expression of this protein is associated with the disease cystic fibrosis. Multiple transcript variants encoding different isoforms have been found for this gene.

GeneCards Summary: S100A8 (S100 Calcium Binding Protein A8) is a Protein Coding gene. Diseases associated with S100A8 include Peptic Ulcer Disease and Duodenal Ulcer. Among its related pathways are MyD88 dependent cascade initiated on endosome and Diseases of Immune System. Gene Ontology (GO) annotations related to this gene include calcium ion binding and RAGE receptor binding. An important paralog of this gene is S100A12.

UniProtKB/Swiss-Prot Summary: S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transferring arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity. Upon infection by human coronavirus SARS-CoV-2, may induce expansion of aberrant immature neutrophils in a TLR4-dependent manner.

8. Cellular Location of Gene Product

Selective nuclear and cytoplasmic expression in squamous epithelia, subsets of cells outside reaction centra of lymphoid tissues and subsets of bone marrow poietic cells. Mainly localized to the intermediate filaments. In addition localized to the cytosol. Predicted location: Secreted, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000143546/subcellular]

9. Mechanistic Information

Summary

S100A8 is involved in the regulation of inflammatory processes and immune response, particularly in the colon where it can induce neutrophil chemotaxis and adhesion [CS: 9]. In conditions like inflammatory bowel disease (IBD), the colon experiences chronic inflammation, leading to tissue damage and altered gut microbiota [CS: 9]. S100A8 responds to this inflammation by increasing the recruitment and adhesion of neutrophils to the inflamed areas [CS: 8]. This action is crucial for controlling the inflammation and initiating tissue repair [CS: 7]. Additionally, S100A8's role in antimicrobial activity becomes significant in the gut during colitis, where it helps in combating microbial infections by chelating zinc ions, essential for microbial growth [CS: 8]. This response is a defense mechanism to prevent further damage and to maintain intestinal integrity [CS: 8].

In cases of colon cancer, S100A8 expression is upregulated, which can be linked to its role in promoting inflammation, a known factor in tumorigenesis [CS: 8]. The protein contributes to the inflammatory microenvironment, which is conducive to cancer development [CS: 8]. S100A8's ability to activate the NADPH-oxidase complex also plays a role here, as this activation can lead to the production of reactive oxygen species (ROS), contributing to DNA damage and cancer progression [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: bone marrow, esophagus, vagina (tissue enhanced) [https://www.proteinatlas.org/ENSG00000143546/tissue]

Cell type enchanced: basal keratinocytes, kupffer cells, serous glandular cells, squamous epithelial cells, suprabasal keratinocytes (cell type enhanced) [https://www.proteinatlas.org/ENSG00000143546/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: