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See related article on page 1600 is observed during epidermal differ- entiation in vivo. This pattern of local- ization is recapitulated in psoriatic (Psoriasin): a Story of Mice tissue, except that the overall S100A7 levels are markedly increased. These and Men properties appear to be biologically 1,2,3,4 1 important, as S100A7 and other S100 Richard L. Eckert and Kathleen C. Lee are transglutaminase substrates S100 proteins are calcium-regulated proteins that regulate fundamental bio- and are incorporated as components of logical processes. S100A7 (psoriasin), functions as a transglutaminase substrate/ the keratinocyte cornified envelope. cornified envelope precursor, signal transduction , chemokine, and anti- Thus, movement to the cell periphery bacterial protein in normal epidermis. S100A7 is markedly increased in epider- would position S100A7 in a location to mal hyperproliferative disorders. The murine homolog of S100A7 and S10015 serve as a substrate of the membrane- has been identified, providing a valuable tool for studying the regulation and anchored cornified envelope assembly function of this protein in epidermis. enzyme type I transglutaminase. Journal of Investigative Dermatology (2006) 126, 1442–1444. doi:10.1038/sj.jid.5700265 In the intracellular compartment, S100A7 appears to interact with epi- dermal fatty acid-binding protein (E- FABP) (Hagens et al., 1999a; Ruse et The S100 proteins are a family of expressed in wound healing, inflam- al., 2003). Although E-FABP is involved more than 20 low-molecular weight matory and hyperproliferative skin in lipid metabolism and transport, the EF hand-containing calcium-regulated diseases, and skin cancer (Broome role of the intracellular S100A7–E- proteins that exist in cells as antiparal- et al., 2003; Madsen et al., 1992; FABP interaction in not known. It is lel homo- and heterodimers. Many of Madsen et al., 1991). S100A7 levels interesting that S100A7 is also found the encoding this family of pro- are increased in , Darier’s dis- in the extracellular environment. It teins are clustered on chromosomal ease, atopic dermatitis, mycosis fun- is reported to be found in psoriatic location 1q21 in the epidermal dif- goides, inflammatory lichen sclerosus plaque exudate, as is its binding part- ferentiation complex (Ridinger et al., et atrophicus, and skin cancer. These ner E-FABP. In this context, S100A7 is 1998). S100 proteins have no known findings suggest an important role for intrinsic enzymatic activity; however, S100A7 in a variety of common skin The sequence the dimer undergoes a diseases (Eckert et al., 2004). conformational change upon calcium S100A7 has several documented will provide an binding. This conformation change roles in epidermis, including function- important new tool exposes protein domains designed to ing as a transglutaminase substrate/ to identify the role of permit S100A7 to interact with spe- cornified envelope precursor, signal cific target proteins, inducing them transduction protein, chemokine, and S100A7 and S100A15 to modulate target protein function antibacterial agent. The relative impor- in normal epidermal and serve as intracellular shuttle pro- tance of these various functions in the | development and in teins (Donato, 2001; Heizmann et context of different environmental al., 2002). Ultimately, activated S100 stimuli or after treatment with prophy- cutaneous diseases and proteins regulate fundamental cell lactic agents is an important area of cancer. processes, including cell proliferation, study. Immunohistological studies of differentiation, and apoptosis (Donato, cultured cells and human epidermis thought to have an antibacterial action 2001; Heizmann et al., 2002). Thirteen reveal that the S100A7 homodimer is (Glaser et al., 2005; Hagens et al., members of this protein family are distributed in the cytoplasm in non- 1999b). In addition, S100A7 may be expressed in various compartments differentiated keratinocytes but redis- released from cultured keratinocytes, in the epidermis (Eckert et al., 2004). tributes to the cell periphery when and it may act as a chemotactic agent S100A7 (psoriasin), S100A8 (MRP8), cultured keratinocytes are challenged (Jinquan et al., 1996), a function that and S100A9 (MRP14) are of particu- with a differentiation stimulus. A simi- has been reported for S100A7 in non- lar interest, as they are highly over- lar redistribution to the cell periphery epidermal tissues. It is important to note that the func- 1Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleve- tion of S100A7 may differ in normal land, Ohio, USA; 2Department of Biochemistry, Case Western Reserve University School of Medicine, versus stressed keratinocytes. The Cleveland, Ohio, USA; 3Department of Dermatology, Case Western Reserve University School of Medi- putative and identified functions of 4 cine, Cleveland, Ohio, USA; and Department of Oncology, Case Western Reserve University School of S100A7 in keratinocytes are shown Medicine, Cleveland, Ohio, USA schematically in Figure 1. In nor- Correspondence: Dr. Richard L. Eckert, Department of Physiology and Biophysics, Room E532, Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, Ohio 44106-4970, USA. mal cultured keratinocytes, S100A7 E-mail: [email protected] expression is increased by agents that

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a in the psoriatic environment? Second, what is the major role of S100A7 in normal keratinocyte differentiation, and does this role change in disease states? Addressing these questions will require extensive human studies as well as studies of the role of S100A7 in murine models. Previous studies have identified several human S100A7 b genes and a encoding human S100A15 (Wolf et al., 2003) — which is 95% identical to S100A7 — that are clustered on 1q21 (Eckert et al., 2004); however, the murine form of the gene had not been previ- ously reported. In this issue, Wolf et al. (2006) describe the isolation of a murine S100 gene that is assigned as the murine homolog to human S100A7 on the basis of the structure of the gene and its position in the genome. The phy- logenic tree suggests that murine S100A15 may be the ancestral gene for the human S100A7 and S100A15 genes. The isolation of this gene is the Figure 1. Regulation of expression and mechanism of S100A7 action in keratinocytes. (a) In normal first identification of a murine mem- keratinocytes, expression of S100A7 is increased by a mechanism that is dependent on protein kinase ber of the S100A7/S100A15 family of C (PKC) and activator protein-1 (AP1) transcription factors. (b) S100A7 exists as a dimer in cells and, in proteins. Wolf et al. (2006) show that response to increased intracellular calcium, forms a complex with two molecules of epidermal fatty acid- murine S100A15 is expressed in the binding protein (E-FABP). This complex (or components of the complex) is speculated to follow at least suprabasal murine epidermal layers. In four possible mechanistic paths: movement to the plasma membrane, where it serves as a transglutaminase addition, murine S100A15 is detected substrate and antibacterial entity; participation in regulation of lipid metabolism; functioning as a cytokine; and functioning as a released antibacterial complex. TG1, type I transglutaminase. as monomers and as high-molecular weight, apparently covalently cross- linked forms, in extracts of cultured human keratinocytes. The accumula- enhance keratinocyte differentiation E-FABP has been implicated as having tion of high-molecular weight forms (phorbol ester, calcium, etc.), a find- a role in lipid metabolism and intra- is increased when the cells are treated ing that is consistent with the presence cellular movement, and so S100A7 with agents (for example, calcium) of S100A7 in the suprabasal differenti- may play a role in shuttling E-FABP that promote keratinocyte differen- ated layers of epidermis (Figure 1a). to the proper subcellular location or tiation and activate type I transgluta- S100A7 is presumed to exist in the facilitating E-FABP activity. In stressed minase. It is striking that formation of cells as a homodimer. In response to keratinocytes, the role of these pro- high-molecular weight forms requires the differentiation stimulus-dependent teins may change. Active export or cell transglutaminase activity and is inhib- increase in intracellular calcium level, breakdown may facilitate the release ited by competitive transglutaminase S100A7 undergoes a conformational of S100A7 and E-FABP, allowing them inhibitors. In addition, these high- change that exposes protein motifs that to act as chemokines and/or antibac- molecular weight bands colocalize interact with E-FABP (Figure 1b). This terial agents. In this context, S100A7 on gels with anti-isopeptide bond interaction is associated with move- expression level may be controlled by immunoreactivity, suggesting that the ment of the S100A7–E-FABP complex agents such as interferon. S100A15 is covalently cross-linked to to the cell periphery, where S100A7 Because this model is speculative, other proteins via isopeptide bonds, and E-FABP are incorporated as corni- key questions regarding the role of the same linkages that are used in cor- fied envelope components. S100 pro- S100A7 in normal differentiation and nified envelope assembly. Expression teins constitute a small fraction of the disease need to be addressed. First, of murine S100A15 is also differen- envelope, suggesting that they do not is S100A7 a key stimulus that leads tiation dependent, as levels increase play a major structural role. Instead, to genesis of the psoriatic phenotype, when cultured murine keratinocytes they may serve as membrane-teth- or is S100A7 a protein whose level is are treated with calcium or phorbol ered antibacterial agents. In addition, increased in response to conditions ester. The signaling pathway required

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for increased production of murine Front Biosci 7:d1356–68 S100 genes in human and mouse. Biochim S100A15 mRNA and protein appears Jinquan T, Vorum H, Larsen CG, Madsen P, Biophys Acta 1448:254–63 to require protein kinase C activity, Rasmussen HH, Gesser B et al. (1996) Ruse M, Broome AM, Eckert RL (2003) S100A7 as the calcium-dependent increase in Psoriasin: a novel chemotactic protein. J (psoriasin) interacts with epidermal fatty Invest Dermatol 107:5–10 acid binding protein and localizes in murine S100A15 level is inhibited by Madsen P, Rasmussen HH, Leffers H, Honore focal adhesion-like structures in cultured protein kinase C inhibitors. Activator B, Celis JE (1992) Molecular cloning and keratinocytes. J Invest Dermatol 121:132–41 protein-1 transcription factors appear expression of a novel keratinocyte protein Wolf R, Mirmohammadsadegh A, Walz M, Lysa to be a downstream target that medi- (psoriasis-associated fatty acid-binding B, Tartler U, Remus R et al. (2003) Molecular ates the protein kinase C-dependent protein [PA-FABP]) that is highly up-regulated cloning and characterization of alternatively in psoriatic skin and that shares similarity to spliced mRNA isoforms from psoriatic skin increase in murine S100A15, as the fatty acid-binding proteins. J Invest Dermatol encoding a novel member of the S100 family. presence of a dominant-negative vari- 99:299–305 FASEB J 17:1969–71 ant of c-Jun inhibits the increase in Madsen P, Rasmussen HH, Leffers H, Honore B, Wolf R, Voscopoulos CJ, FitzGerald PC, murine S100A15. Dejgaard K, Olsen E et al. (1991) Molecular Goldsmith P, Cataisson C, Gunsior M et al. It is gratifying to have confirmation cloning, occurrence, and expression of a (2006) The mouse S100A15 ortholog parallels novel partially secreted protein “psoriasin” that S100A7 expression, regulation, genomic organization, structure, gene that is highly up-regulated in psoriatic skin. J expression, and protein-processing pattern and subcellular localization are simi- Invest Dermatol 97:701–12 of the human S100A7/A15 subfamily during lar in human and murine epidermis. Ridinger K, Ilg EC, Niggli FK, Heizmann CW, epidermal maturation. J Invest Dermatol Moreover, it is clear that the availabil- Schafer BW (1998) Clustered organization of 126:1600–08 ity of the S100A15 sequence will pro- vide an important new tool to identify the role of S100A7 and S100A15 in See related article on page 1534 normal epidermal development and in cutaneous diseases and cancer. CONFLICT OF INTEREST HLA-Independent Antibacterial Host The authors state no conflict of interest. Response toward Th1 Immunity ACKNOWLEDGMENTS This work used the facilities of the Skin Diseases Research Center of Northeast Ohio (National Mediated by IL-12: a New Concept for Institutes of Health grant AR39750) and was supported by a grant from the National Institutes of Health (to R.L.E.). the Pathogenesis of Adamantiades–

REFERENCES Behçet’s Disease Broome AM, Ryan D, Eckert RL (2003) S100 1,2 protein subcellular localization during Christos C. Zouboulis epidermal differentiation and psoriasis. J Histochem Cytochem 51:675–85 Yanagihori et al. found an HLA-independent higher frequency of IL-12B promot- Donato R (2001) S100: a multigenic family of er polymorphism in Adamantiades–Behçet’s disease (ABD) patients than in con- calcium-modulated proteins of the EF-hand trols. Stimulation with streptococcal antigens specifically increased expression type with intracellular and extracellular functional roles. Int J Biochem Cell Biol of patients’ peripheral blood mononuclear cells IL-12 p40/p70. The authors pro- 33:637–68 vide evidence for an antibacterial host response toward T-helper type 1 immunity Eckert RL, Broome AM, Ruse M, Robinson N, mediated by IL-12 in patients with ABD, which is HLA independent. Ryan D, Lee K (2004) S100 proteins in the Journal of Investigative Dermatology (2006) 126, 1444–1447. doi:10.1038/sj.jid.5700281 epidermis. J Invest Dermatol 123:23–33 Glaser R, Harder J, Lange H, Bartels J, Christophers E, Schroder JM (2005) Antimicrobial psoriasin (S100A7) protects human skin from infection. Adamantiades–Behçet’s disease (ABD) is involvement, whereas mucocutaneous Nat Immunol 6:57–64 a multisystemic, inflammatory disorder lesions exhibit histological changes of Hagens G, Masouye I, Augsburger E, Hotz R, of unknown etiology with hyperergic vascular reaction or vasculitis. Linked Saurat JH, Siegenthaler G (1999a) Calcium- behavior and a chronic recurrent course intrinsic and extrinsic factors are con- binding protein S100A7 and epidermal-type (Sakane et al., 1999). It is characterized sidered to contribute to the develop- fatty acid-binding protein are associated in the cytosol of human keratinocytes. Biochem by oral and genital ulcerations, various ment of the disease, and this has led to J 339:419–27 cutaneous manifestations, and ocular the concept of environmental triggering Hagens G, Roulin K, Hotz R, Saurat JH, Hellman U, Siegenthaler G (1999b) Probable 1Departments of Dermatology and Immunology, Dessau Medical Center, Dessau, Germany; and interaction between S100A7 and E-FABP 2Laboratory of Biogerontology, Dermato-Pharmacology and Dermato-Endocrinology, Institute of Clinical in the cytosol of human keratinocytes from Pharmacology and Toxicology, Charité Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, psoriatic scales. Mol Cell Biochem 192:123–8 Germany Heizmann CW, Fritz G, Schafer BW (2002) S100 Correspondence: Dr. Christos C. Zouboulis, Departments of Dermatology and Immunology, Dessau proteins: structure, functions and pathology. Medical Center, Auenweg 38, 06847 Dessau, Germany. E-mail: [email protected]

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