S100 proteins & skin

M.Y.Abdel-Mawla Zagazig

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S100 Proteins and S100 Proteins and Their Role in Some Their Role in Some

Dermatological Dermatological DiseasesDiseases

ByByM.Y.ABDEL-MAWLA,MDM.Y.ABDEL-MAWLA,MDZAGAZIG FACULTY OF ZAGAZIG FACULTY OF

MEDICINE,EGYPTMEDICINE,EGYPT

S100 Proteins

Structure and Functions

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S100 proteins are calcium-binding proteins.

The protein complex was termed “S100” because of its solubility in 100% ammonium sulfate solution.

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S100 proteins are characterized by a common structure including two hands (helix-loop-helix calcium-binding domains)

These are separated by a hinge region and flanked by amino- and carboxy-terminal domains .

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S100 proteins are proposed to have intracellular and extracellular roles in the regulation of many diverse processes such as:

1. Protein phosphorylation.2. Cell growth and motility. 3. Cell-cycle regulation.4. Transcription. 5. Differentiation and cell survival. These functions may or may

not be calcium dependent.

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Some S100 protein genes are located within the epidermal differentiation complex on human chromosome 1q21.

Some S100 proteins are expressed in normal and/or diseased epidermis.

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Profilaggrin which is expressed within keratohyaline granule,has an S100- like domain.

During epidermal differentiation,profilaggrin is cleaved by protease enzymes.

The cleaved S100 domain enter into the nucleus to exert an additional role in differentiation.

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Structure of Proflaggrin

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Role of S100 proteins in epidermis biology

Some S100 proteins play a role in remodeling occurring during keratinocyte differentiation.

Some S100 proteins (e.g. S100A10, S100A11) are transglutaminase substrates.

They cross link in the cornified envelope. S100 proteins (S100A7,S100A8 and

S100A9) exhibit pro-inflammatory properties.

Some proteins (e.g. S100A7)have an antimicrobial potential.

Some S100 proteins function in formation of calcium channels.

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Role of S100 proteins in epidermis biology

Some S100 proteins play a role in remodeling occurring during keratinocyte differentiation.

Some S100 proteins (e.g. S100A10, S100A11) are transglutaminase substrates.

They cross link in the cornified envelope. S100 proteins (S100A7,S100A8 and

S100A9) exhibit pro-inflammatory properties.

Some proteins (e.g. S100A7)have an antimicrobial potential.

Some S100 proteins function in formation of calcium channels.

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Calcium and S100 proteins

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S100 Proteins Functions

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S100 Proteins in Epidermis

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S100 proteins in epidermis 

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In response to oxidative stress stimuli. There is a translocation of S100 proteins inside keratinocytes.

For example, upon exposure to oxidative stress S100A2 is translocated from nucleus into the cytoplasm.

This translocation is an early marker of oxidative stress induced keratinocytes apoptosis.

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Ultraviolet (UV) -A causes an oxidising enviroment, which induces translocation of S100A8 and S100A9 into the cytoplasm of keratinocytes.

Translocation and extra cellular translation of S100 protein influence function.

S100 proteins may move to locate their target proteins or they may function to carry their target proteins to a new intra or extra cellular location

Protein targets of S100 proteins

S100 Proteins and Their Role in Some

Skin Diseases

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S100 Proteins in Atopic Dermatitis Atopic skin lesions revealed

altered expression of genes located within the EDC, in particular up regulation of S100A7 and S100A8 and down regulation of loricrin and filaggrin.

Decreased levels of both filaggrin and loricrin and increased levels of S100A7 and S100A8 expression have already been observed in skin biopsy specimens of patients with AD.

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S100 Proteins in Psoriasis Toll-like receptors may recognize

pathogens and thereby orchestrate a vicious circle of innate immune response genes, including AMPs.

Such AMPs, including human S100A7 (psoriasin) and human S100A15, not only have antimicrobial activity, but also act as chemokines and can alter adaptive immune cell function, including those of dendritic cells (DCs) and T cells.

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Schematic summary of important innate immunity events in the pathophysiology of psoriasis

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S100 Proteins in Kawazaki(KD) Disease

S100A8 and A9 were tested as potential biomarkers for KD and coronary artery sequelae.

These proteins form heterodimers and are secreted by neutrophils and monocytes in response to inflammatory signaling cascades.

Serum levels of S100A8 and A9 were markedly elevated in KD patients compared with healthy controls.

S100 Proteins and Tumors

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Some S100 proteins such as S100A2, S100A9 and S100A11 are tumor suppressor .

Some S100 Protein as S100A4 are inhibitor of tumor suppressor P53.

Some S100 Proteins interact with matrix metalloproteins,cytoskeletal proteins and other proteins.

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S100 proteins and possible cancer diseases

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S100A is identified 79% of all clinical specimens and 75% of pigmented tumors.

In humans, polyclonal S100 is expected to stain nearly 100% of all melanocytic tumors.

S100 negative tumors have been identified in the amelanotic tumors.

S100B expression level is highest in grade IV melanoma and has been associated with the presence of metastases and reduced survival.

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S100 Protein immune staging in melanocytic melanoma 

Biomarker Common nevi Spitz nevus Melanoma

S100A Protein 56% weak dermal

100% strong, diffuse

33% weak dermal

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Marker Sensitivity/specificity

melanoma Carcinoma Sarcoma/soft tissue tumors

Epithelioidcells

Spindle cells

S100 Proteins

<95%/75%-87%

+ + (98% Sensitivity)

-(+Myoepithelial Carcinoma)

+/-

S100 Protein immune staging in melanocytic nevi and their tumor mimics

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 Neural proliferation

S100 

Neurofilament

Epithelial membrane

antigen (EMA)

 Other

Traumatic neuroma + + + Neuron specific enolase positive

Palisaded encapsulated neuroma

 +

 +

+ For capsule  

 Schwannoma

 +

 -

+ for capsule only  Vimentin positive

Neurofibroma + Variable -  

Plexiform neurofibroma  +

 +

 Neurothekeoma

 +

 -

 Variable

Vimentin variable;usually EMA negative

Cellular Neurothekeoma -   - CD57 positive;Ki-Mip positive

 perineurioma

 -

 -

+ Vimentin positive;neuron-specific enolase negative

 Malignant peripheral nerve sheath tumor

  +

  +

Variable

Vimentin variable;cytokeratin negative ;neuron-specific

enolase positive

Primitive neuroectodermal tumor

 + If differentiated

    Neuron-specific enolase positive;CD99 positive

Granular cell tumor +     Neuron-specific enolase positive

+ = Positive: - = negative.

Staining with S100 protein and other marker of neural hyperplasias and neoplasms

How to detect S100 Proteins?

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Analytical methods such as immunoradiometric assay (IRMA), mass spectroscopy, western blot, ELISA (enzyme linked immunosorbent assay) and quantitative polymerase chain reaction(PCR), can detect S100 changes in immunohistochemical expression or in serum concentration.

  Anti S100 antibody (CONFIRM®

Ventana Medical Systems, Inc.USA) is used .

Summary and Conclusion

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S100 Proteins are calcium dependent structures.

They play an important role in epidermal differentiation and cornification.

They may play a role in pathogenesis of some skin diseases (e.g. Psoriasis).

S100 Proteins are biomarkers for melanotic skin tumors.

S100 Proteins can be detected in tissue and serum using monoclonal antibody technique.

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