S100B explained

S100 calcium-binding protein B (S100B) is a protein of the S100 protein family.

S100 proteins are localized in the cytoplasm and 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; however, this gene is located at 21q22.3.

Function

S100B is glial-specific and is expressed primarily by astrocytes, but not all astrocytes express S100B. It has been shown that S100B is only expressed by a subtype of mature astrocytes that ensheath blood vessels and by NG2-expressing cells.^[1]

This protein may function in neurite extension, proliferation of melanoma cells, stimulation of Ca²⁺ fluxes, inhibition of PKC-mediated phosphorylation, astrocytosis and axonal proliferation, and inhibition of microtubule assembly. In the developing CNS it acts as a neurotrophic factor and neuronal survival protein. In the adult organism it is usually elevated due to nervous system damage, which makes it a potential clinical marker.

Clinical significance

Chromosomal rearrangements and altered expression of this gene have been implicated in several neurological, neoplastic, and other types of diseases, including Alzheimer disease, Down syndrome, epilepsy, amyotrophic lateral sclerosis, schwannoma, melanoma, and type I diabetes mellitus.^[2]

It has been suggested that the regulation of S100B by melittin has potential for the treatment of epilepsy.^[3]

Diagnostic use

S100B is secreted by astrocytes or can spill from injured cells and enter the extracellular space or bloodstream. Serum levels of S100B increase in patients during the acute phase of brain damage. Over the last decade, S100B has emerged as a candidate peripheral biomarker of blood–brain barrier (BBB) permeability and CNS injury. Elevated S100B levels accurately reflect the presence of neuropathological conditions including traumatic head injury or neurodegenerative diseases. Normal S100B levels reliably exclude major CNS pathology. Its potential clinical use in the therapeutic decision making process is substantiated by a vast body of literature (citation?) validating variations in serum 100B levels with standard modalities for prognosticating the extent of CNS damage: alterations in neuroimaging, cerebrospinal pressure, and other brain molecular markers (neuron specific enolase and glial fibrillary acidic protein). However, more importantly, S100B levels have been reported to rise prior to any detectable changes in intracerebral pressure, neuroimaging, and neurological examination findings. Thus, the major advantage of using S100B is that elevations in serum or CSF levels provide a sensitive measure for determining CNS injury at the molecular level before gross changes develop, enabling timely delivery of crucial medical intervention before irreversible damage occurs. S100B serum levels are elevated before seizures suggesting that BBB leakage may be an early event in seizure development.^[4] An extremely important application of serum S100B testing is in the selection of patients with minor head injury who do not need further neuroradiological evaluation, as studies comparing CT scans and S100B levels have demonstrated S100B values below 0.12 ng/mL are associated with low risk of obvious neuroradiological changes (such as intracranial hemorrhage or brain swelling) or significant clinical sequelae.^[5] The excellent negative predictive value of S100B in several neurological conditions is due to the fact that serum S100B levels reflect blood–brain barrier permeability changes even in absence of neuronal injury.^{[6] [7]} In addition, S100B, which is also present in human melanocytes, is a reliable marker for melanoma malignancy both in bioptic tissue and in serum.^{[8] [9]}

Interactions

S100B has been shown to interact with:

• AHNAK,^[10]
• IMPA1,^[11]
• IQGAP1,^[12]
• MAPT,^{[13] [14]} and
• P53,^[15]
• PGM1,^[16]
• S100A1,^{[17] [18]}
• S100A6,
• S100A11,^[19]
• VAV1.^[20]

Further reading

• Schäfer BW, Heizmann CW . The S100 family of EF-hand calcium-binding proteins: functions and pathology . Trends Biochem. Sci. . 21 . 4 . 134–40 . 1996 . 8701470 . 10.1016/S0968-0004(96)80167-8 .
• Garbuglia M, Verzini M, Sorci G, Bianchi R, Giambanco I, Agneletti AL, Donato R . The calcium-modulated proteins, S100A1 and S100B, as potential regulators of the dynamics of type III intermediate filaments . Braz. J. Med. Biol. Res. . 32 . 10 . 1177–85 . 2000 . 10510252 . 10.1590/s0100-879x1999001000001 . free .
• Rothermundt M, Peters M, Prehn JH, Arolt V . S100B in brain damage and neurodegeneration . Microsc. Res. Tech. . 60 . 6 . 614–32 . 2003 . 12645009 . 10.1002/jemt.10303 . 25531839 .
• Michetti F, Gazzolo D . S100B testing in pregnancy . Clin. Chim. Acta . 335 . 1–2 . 1–7 . 2004 . 12927678 . 10.1016/S0009-8981(03)00243-2 .
• Raabe A, Kopetsch O, Woszczyk A, Lang J, Gerlach R, Zimmermann M, Seifert V . Serum S-100B protein as a molecular marker in severe traumatic brain injury . Restor. Neurol. Neurosci. . 21 . 3–4 . 159–69 . 2004 . 14530578 .
• Sen J, Belli A . S100B in neuropathologic states: the CRP of the brain? . J. Neurosci. Res. . 85 . 7 . 1373–80 . 2007 . 17348038 . 10.1002/jnr.21211 . 25932611 .
• Morii K, Tanaka R, Takahashi Y, Minoshima S, Fukuyama R, Shimizu N, Kuwano R . Structure and chromosome assignment of human S100 alpha and beta subunit genes . Biochem. Biophys. Res. Commun. . 175 . 1 . 185–91 . 1991 . 1998503 . 10.1016/S0006-291X(05)81218-5 .
• Allore RJ, Friend WC, O'Hanlon D, Neilson KM, Baumal R, Dunn RJ, Marks A . Cloning and expression of the human S100 beta gene . J. Biol. Chem. . 265 . 26 . 15537–43 . 1990 . 10.1016/S0021-9258(18)55430-2 . 2394738 . free .
• Duncan AM, Higgins J, Dunn RJ, Allore R, Marks A . Refined sublocalization of the human gene encoding the beta subunit of the S100 protein (S100B) and confirmation of a subtle t(9;21) translocation using in situ hybridization . Cytogenet. Cell Genet. . 50 . 4 . 234–5 . 1989 . 2530061 . 10.1159/000132767 .
• Baudier J, Cole RD . Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II . J. Biol. Chem. . 263 . 12 . 5876–83 . 1988 . 10.1016/S0021-9258(18)60647-7 . 2833519 . free .
• Allore R, O'Hanlon D, Price R, Neilson K, Willard HF, Cox DR, Marks A, Dunn RJ . Gene encoding the beta subunit of S100 protein is on chromosome 21: implications for Down syndrome . Science . 239 . 4845 . 1311–3 . 1988 . 2964086 . 10.1126/science.2964086 . 1988Sci...239.1311A .
• Jensen R, Marshak DR, Anderson C, Lukas TJ, Watterson DM . Characterization of human brain S100 protein fraction: amino acid sequence of S100 beta . J. Neurochem. . 45 . 3 . 700–5 . 1985 . 4031854 . 10.1111/j.1471-4159.1985.tb04048.x . 46028228 .
• Baudier J, Glasser N, Haglid K, Gerard D . Purification, characterization and ion binding properties of human brain S100b protein . Biochim. Biophys. Acta . 790 . 2 . 164–73 . 1984 . 6487634 . 10.1016/0167-4838(84)90220-6 .
• Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O . Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence . Nature . 377 . 6547 Suppl . 3–174 . 1995 . 7566098 . .
• Schäfer BW, Wicki R, Engelkamp D, Mattei MG, Heizmann CW . Isolation of a YAC clone covering a cluster of nine S100 genes on human chromosome 1q21: rationale for a new nomenclature of the S100 calcium-binding protein family . Genomics . 25 . 3 . 638–43 . 1995 . 7759097 . 10.1016/0888-7543(95)80005-7 .
• Reeves RH, Yao J, Crowley MR, Buck S, Zhang X, Yarowsky P, Gearhart JD, Hilt DC . Astrocytosis and axonal proliferation in the hippocampus of S100b transgenic mice . Proc. Natl. Acad. Sci. U.S.A. . 91 . 12 . 5359–63 . 1994 . 8202493 . 43994 . 10.1073/pnas.91.12.5359 . 1994PNAS...91.5359R . free .
• Engelkamp D, Schäfer BW, Mattei MG, Erne P, Heizmann CW . Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for the two previously unreported calcium-binding proteins S100D and S100E . Proc. Natl. Acad. Sci. U.S.A. . 90 . 14 . 6547–51 . 1993 . 8341667 . 46969 . 10.1073/pnas.90.14.6547 . 1993PNAS...90.6547E . free .
• Peña LA, Brecher CW, Marshak DR . beta-Amyloid regulates gene expression of glial trophic substance S100 beta in C6 glioma and primary astrocyte cultures . Brain Res. Mol. Brain Res. . 34 . 1 . 118–26 . 1997 . 8750867 . 10.1016/0169-328X(95)00145-I .
• Argandoña EG, Bengoetxea H, Lafuente JV . Physical exercise is required for environmental enrichment to offset the quantitative effects of dark-rearing on the S-100β astrocytic density in the rat visual cortex . . 215 . 2 . 132–40 . 2009 . 19500177 . 2740960 . 10.1111/j.1469-7580.2009.01103.x .
• Landar A, Caddell G, Chessher J, Zimmer DB . Identification of an S100A1/S100B target protein: phosphoglucomutase . Cell Calcium . 20 . 3 . 279–85 . 1997 . 8894274 . 10.1016/S0143-4160(96)90033-0 .

Notes and References

1. Wang DD, Bordey A . The astrocyte odyssey . Prog. Neurobiol. . 86 . 4 . 342–67 . December 2008 . 18948166 . 2613184 . 10.1016/j.pneurobio.2008.09.015 .
2. Web site: Entrez Gene: S100B S100 calcium binding protein B.
3. Verma N, Karmakar M, Singh KP, Smita S . February 2013 . Structural and Dynamic Insights into S100B Protein Activity Inhibition by Melittin for the Treatment of Epilepsy . International Journal of Computer Applications . NSAAILS . 975–8887 . 55–60 .
4. Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D . Seizure-promoting effect of blood–brain barrier disruption . Epilepsia . 48 . 4 . 732–42 . April 2007 . 17319915 . 10.1111/j.1528-1167.2007.00988.x . 4135474 .
5. Zongo D, Ribéreau-Gayon R, Masson F, Laborey M, Contrand B, Salmi LR, Montaudon D, Beaudeux JL, Meurin A, Dousset V, Loiseau H, Lagarde E . S100-B protein as a screening tool for the early assessment of minor head injury . Annals of Emergency Medicine . 59 . 1 . 209–218 . 2012 . 21944878 . 10.1016/j.annemergmed.2011.07.027 .
6. Czeisler BM, Janigro D . Reading and writing the blood–brain barrier: relevance to therapeutics . Recent Patents on CNS Drug Discovery . 1 . 2 . 157–73 . June 2006 . 18221201 . 10.2174/157488906777452712 .
7. Marchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D . Peripheral markers of blood–brain barrier damage . Clinica Chimica Acta . 342 . 1–2 . 1–12 . April 2004 . 15026262 . 10.1016/j.cccn.2003.12.008 .
8. Michetti F, Corvino V, Geloso MC, Lattanzi W, Bernardini C, Serpero L, Gazzolo D . The S100B protein in biological fluids: more than a lifelong biomarker of brain distress . J. Neurochem. . 120 . 5 . 644–59 . March 2012 . 22145907 . 10.1111/j.1471-4159.2011.07612.x . 205624114 . free .
9. Cocchia D, Michetti F, Donato R . Immunochemical and immuno-cytochemical localization of S-100 antigen in normal human skin . Nature . 294 . 5836 . 85–7 . November 1981 . 7290214 . 10.1038/294085a0 . 1981Natur.294...85C . 4333999 .
10. Gentil BJ, Delphin C, Mbele GO, Deloulme JC, Ferro M, Garin J, Baudier J . The giant protein AHNAK is a specific target for the calcium- and zinc-binding S100B protein: potential implications for Ca2+ homeostasis regulation by S100B . J. Biol. Chem. . 276 . 26 . 23253–61 . June 2001 . 11312263 . 10.1074/jbc.M010655200 . free .
11. Vig PJ, Shao Q, Subramony SH, Lopez ME, Safaya E . Bergmann glial S100B activates myo-inositol monophosphatase 1 and Co-localizes to purkinje cell vacuoles in SCA1 transgenic mice . Cerebellum . 8 . 3 . 231–44 . September 2009 . 19593677 . 3351107 . 10.1007/s12311-009-0125-5 .
12. Mbele GO, Deloulme JC, Gentil BJ, Delphin C, Ferro M, Garin J, Takahashi M, Baudier J . The zinc- and calcium-binding S100B interacts and co-localizes with IQGAP1 during dynamic rearrangement of cell membranes . J. Biol. Chem. . 277 . 51 . 49998–50007 . December 2002 . 12377780 . 10.1074/jbc.M205363200 . free .
13. Yu WH, Fraser PE . S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease . J. Neurosci. . 21 . 7 . 2240–6 . April 2001 . 11264299 . 6762409 . 10.1523/JNEUROSCI.21-07-02240.2001.
14. Baudier J, Cole RD . Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II . J. Biol. Chem. . 263 . 12 . 5876–83 . April 1988 . 10.1016/S0021-9258(18)60647-7 . 2833519 . free .
15. Lin J, Yang Q, Yan Z, Markowitz J, Wilder PT, Carrier F, Weber DJ . Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells . J. Biol. Chem. . 279 . 32 . 34071–7 . August 2004 . 15178678 . 10.1074/jbc.M405419200 . free .
16. Landar A, Caddell G, Chessher J, Zimmer DB . Identification of an S100A1/S100B target protein: phosphoglucomutase . . 20 . 3 . 279–85 . September 1996 . 8894274 . 10.1016/S0143-4160(96)90033-0 .
17. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
18. Yang Q, O'Hanlon D, Heizmann CW, Marks A . Demonstration of heterodimer formation between S100B and S100A6 in the yeast two-hybrid system and human melanoma . Exp. Cell Res. . 246 . 2 . 501–9 . February 1999 . 9925766 . 10.1006/excr.1998.4314 .
19. Deloulme JC, Assard N, Mbele GO, Mangin C, Kuwano R, Baudier J . S100A6 and S100A11 are specific targets of the calcium- and zinc-binding S100B protein in vivo . J. Biol. Chem. . 275 . 45 . 35302–10 . November 2000 . 10913138 . 10.1074/jbc.M003943200 . free .
20. Fackler OT, Luo W, Geyer M, Alberts AS, Peterlin BM . Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions . Mol. Cell . 3 . 6 . 729–39 . June 1999 . 10394361 . 10.1016/S1097-2765(01)80005-8 . free .