|Year : 2018 | Volume
| Issue : 7 | Page : 100-106
S100 proteins: An emerging cynosure in pregnancy & adverse reproductive outcome
Rachna Verma, Priyanka Verma, Snehil Budhwar, Kiran Singh
Department of Molecular & Human Genetics, Banaras Hindu University, Varanasi, India
|Date of Submission||09-Mar-2018|
|Date of Web Publication||3-Apr-2019|
Dr Kiran Singh
Department of Molecular & Human Genetics, Banaras Hindu University, Varanasi 221 005, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
S100 proteins are calcium (Ca2+)-binding proteins and these have an important function in progression, manifestation and therapeutic aspects of various inflammatory, metabolic and neurodegenerative disorders. Based on their involvement in intracellular or extracellular regulatory effects, S100 proteins are classified into three subgroups: one subgroup is specialized in exerting only intracellular effects, other performs both intracellular and extracellular functions and the third subgroup members only display extracellular regulatory effects. S100 proteins are expressed particularly in vertebrates and have cell-specific expression. Functionally, S100 proteins act through their surface receptors and regulate cell functions in autocrine or paracrine mode. Receptor for advanced glycation end products (RAGEs) and toll-like receptor 4 are the main surface receptors. S100 proteins participate in the regulation of cellular differentiation, proliferation, apoptosis and inflammation along with Ca2+ homeostasis, energy metabolism and cellular migration, and perform the respective functions through their interaction with transcription factors, nucleic acids, enzymes, receptors, cytoskeleton system, etc. Currently, their role in adverse pregnancy outcomes and compromised reproductive health is being explored. These proteins are present in amniotic fluid, endometrium tissue and foetal brain; therefore, it is quite likely that alterations in the expression levels of S100 family members will be affecting the particular function they are involved in and ultimately affecting the pregnancy in adverse manner. The current review discusses about an association of S100 proteins in pregnancy disorders such as endometriosis, intrauterine growth retardation and miscarriage.
Keywords: Calcium signalling - early pregnancy loss - high-risk pregnancy - implantation - inflammation - intrauterine growth retardation
|How to cite this article:|
Verma R, Verma P, Budhwar S, Singh K. S100 proteins: An emerging cynosure in pregnancy & adverse reproductive outcome. Indian J Med Res 2018;148, Suppl S1:100-6
|How to cite this URL:|
Verma R, Verma P, Budhwar S, Singh K. S100 proteins: An emerging cynosure in pregnancy & adverse reproductive outcome. Indian J Med Res [serial online] 2018 [cited 2020 May 31];148, Suppl S1:100-6. Available from: http://www.ijmr.org.in/text.asp?2018/148/7/100/255410
Rachna Verma & Priyanka Verma contributed equally.
| Introduction|| |
Early miscarriage and pregnancy-associated problems are of major concern. The reason behind this is not only genetical or physiological but also environmental and modern lifestyle. Moderate levels of inflammatory reactions are also pre-requisite during the first trimester of pregnancy for implantation and embryo development. These early stages of pregnancy resemble 'an open wound'. For invasion and proper blood supply of embryo neovascularization and tissue remodelling occur during early gestational weeks of pregnancy ,. An appropriate tuning of anti-inflammatory and inflammatory mediators is required for adequate repair of the uterine epithelium and the removal of cellular debris. Thus, this critical period of pregnancy is marked by expression of specific cytokines and adhesion molecules by both foetal and maternal side ensuring successful pregnancy. Any alteration and dysfunction of this balanced inflammatory milieu and any perturbation or disturbance in this during the critical period result in miscarriage or pregnancy-associated complications .
Earlier studies in mice and human revealed the role of important calcium (Ca 2+)-binding S100 proteins in pregnancy-related complications ,. This group of proteins helps in the recruitment of leucocytes at inflammatory site and functions like cytokines . These proteins regulate a variety of cellular functions such as cellular differentiation, cell cycle progression and energy intracellular signal transduction by interacting with several other mediatory proteins . S100 proteins were found to be tumorigenic in function and get elevated in several cancer and melanoma cases . An earlier study in human also showed elevated level of S100 group proteins in high-risk pregnancy cases, in amniotic fluid and cord blood of foetus with brain damage . The role of S100 protein in immunomodulation of high-risk pregnancy cases is an active area of research and clinical investigation. This review focuses on new advances regarding the role of S100 protein in diagnosis and treatment of high-risk pregnancies.
| S100 Protein Structure and Function|| |
Ca2+ regulates several cellular processes and acts as a messenger . Many Ca 2+-binding proteins, having the EF-hand structural motif, make Ca 2+ signalling network in combination with many molecular components . S100 proteins are the largest subgroup within this family of Ca 2+-binding proteins and found to be involved in several diseases such as rheumatoid arthritis, acute inflammatory lesions, cardiomyopathy, Alzheimer's disease and cancer ,.
S100 proteins are acidic, Ca 2+-binding proteins initially identified in the brain of several mammalian species and called S100 because of their solubility in 100 per cent ammonium sulphate ,. Genes responsible for the synthesis of most S100 proteins are located on human chromosomes 1q21. Initially, S100 proteins were found to be located in glial cells and used as a marker of glial cell differentiation and mammalian brain development ,,. S100 protein family has 21 members having the same basic structural moiety but entirely different function, and are found in cerebrospinal fluid, urine, serum, seminal plasma and saliva mainly in active disease states. These proteins are found to be present in Ca 2+ free (apo); Ca 2+-bound and target bound states as a symmetric dimer, with each monomer containing two EF-hand motifs . The EF-hand motif on N-terminal site contains helix I with pseudo Ca 2+-binding site, and the EF-hand of C-terminal is associated with helix III, helix IV and second Ca 2+-binding site [Figure 1].
|Figure 1: Schematic diagram represents the chromosomal location, structure and various functions of S100 proteins. Source: Refs 14, 18.|
Click here to view
S100 proteins undergo structural and conformational changes on binding with Ca 2+, and this conformational change allows interaction of these proteins with target molecules. Activated S100 proteins perform all cellular functions by both extracellular and intracellular methods [Table 1]. All S100 proteins function in the form of dimmers, and only S100G protein acts as monomer . A few hetero-dimmers are also reported: S100A1/B, S100A8/A9, S100A1/A4 and S100A1/P ,. S100 proteins can also form active tetramers, hexamers or larger oligomers (S100B , S100A4, S100A8/A9 and S100 A12).
| S100 Receptors|| |
Function of S100 proteins is determined by their oligomeric forms and their respective binding partners . Extracellular S100 proteins act via activation of surface receptors such as G protein-coupled receptors, receptor for advanced glycation end products (RAGEs) and toll-like receptors and aid in regulatory processes such as cell proliferation, differentiation and migration in normal as well as different pathological conditions. Intracellular S100 proteins also act via interaction with different target enzymes, cytoskeleton subunits, receptors and transcription factors or nucleic acids regulate Ca 2+ homeostasis, energy metabolism and cellular differentiation.
| Role of S100 Proteins in High-Risk Pregnancy Cases|| |
In maternal endometrium, S100 proteins are expressed by both immune cells and non-immune cells. A few groups of S100 proteins such as S100A8, S100A9 and S100A12 are mainly secreted from myeloid origin of immune cells such as granulocytes, monocytes and early stages of macrophages . As myeloid origin cells are well known as crucial regulators for other immune cells (T, Treg, uNK and non-inflammatory macrophages and neutrophils cells) in successful pregnancy, any alteration in inflammatory or immunomodulatory stage may change S100 protein levels [Figure 2]. Some non-immune cells such as mice placenta and ovaries of cow and pig have been reported to secrete some S100 group proteins such as S100A1, S100A6, S100A9 and S100A8,.
|Figure 2: Schematic diagram represents interaction of S100 proteins with immune cells for the regulation of various hallmark processes of pregnancy. IFN-γ, interferon gamma; IL, interleukin; TH, T helper; TNF-α, tumor necrosis factor alpha; uNK, uterine natural killer. Source: Refs 4, 47.|
Click here to view
S100 proteins regulate embryo implantation, intrauterine growth and normal foetal brain development during pregnancy. S100 family proteins have been found to be dysregulated in various endometrial diseases [Table 2]. S100A8 proteins are found to be down regulated in receptive phase of endometrium . S100A8 protein recruits mouse and human neutrophils and macrophages at the site of inflammation . Endometrial epithelium and stromal cells also showed expression of S100A10 protein during the implantation window and found to play an important role in endometrial receptivity . The expression of these proteins have been found to be down regulated in the endometrium of infertile patients ,. This is the reason behind the failure of 30 per cent of embryo implantation in assisted reproduction.
|Table 2: Altered expression profile of S100 proteins in various human pregnancy-related diseases|
Click here to view
A study conducted by Passey et al showed that S100A8 knockout gene in mice caused a late embryonic lethality and suggested its role in fetomaternal tolerance. A study on transcriptome-based analysis in equine pregnancy revealed that S100A6 protein was expressed in conceptus side, and S100A2, S100A4, S100A6 and S100A8 were present in maternal endometrium on day 16 in mare . A key role of these proteins has been suggested in epidermal growth factor-stimulated embryo adhesion, acquisition of endometrial receptivity, immunotolerance, apoptosis of dead endometrial epithelial cells and prolactin secretion, a marker for onset of decidualization ,. S100 β protein is also found to be up regulated in trisomy cases, and their upregulation is an indicator of a brain lesion in developing foetus . Thus, monitoring of S100 protein could be helpful in the detection of brain distress in intrauterine growth-retarded (IUGR) foetuses . In preeclampsia and IUGR cases, amniotic fluid S100B protein concentration was found to be elevated .
| Conclusion|| |
The present review summarizes the role of S100 proteins in high-risk pregnancy cases along with its structure and mechanism of action. This also covers the importance of S100 proteins as a main player of successful implantation, embryonic growth and birth of physically and mentally healthy child. The optimal expression and signalling of S100 proteins, at particular stages of pregnancy is a pre-requisite for avoiding high-risk pregnancy cases and can serve as therapeutic target and prognostic biomarker in pregnancy-related complications.
Financial support & sponsorship: The first author (RV) and the second author (PV) acknowledge the Department of Biotechnology, New Delhi, India, for providing financial assistance in the form of Research Associateship and Senior Research Fellowship, respectively. The third author (SB) thanks the University Grant Commission, New Delhi, India, for providing financial assistance in the form of Senior Research Fellowship.
Conflicts of Interest: None.
| References|| |
Mor G, Cardenas I. The immune system in pregnancy: A unique complexity. Am J Reprod Immunol
Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: The role of the immune system at the implantation site. Ann N Y Acad Sci
Kwak-Kim J, Yang KM, Gilman-Sachs A. Recurrent pregnancy loss: A disease of inflammation and coagulation. J Obstet Gynaecol Res
Nair RR, Khanna A, Singh K. Association of increased S100A8 serum protein with early pregnancy loss. Am J Reprod Immunol
Passey RJ, Williams E, Lichanska AM, Wells C, Hu S, Geczy CL, et al.
A null mutation in the inflammation-associated S100 protein S100A8 causes early resorption of the mouse embryo. J Immunol
Kanamori T, Takakura K, Mandai M, Kariya M, Fukuhara K, Sakaguchi M, et al.
Increased expression of calcium-binding protein S100 in human uterine smooth muscle tumours. Mol Hum Reprod
Michetti F, Gazzolo D. S100B testing in pregnancy. Clin Chim Acta
Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol
Kawasaki H, Nakayama S, Kretsinger RH. Classification and evolution of EF-hand proteins. Biometals
Van Eldik LJ, Griffin WS. S100 beta expression in Alzheimer's disease: Relation to neuropathology in brain regions. Biochim Biophys Acta
Heizmann CW, Cox JA. New perspectives on S100 proteins: A multi-functional Ca(2+)-, Zn(2+)- and Cu(2+)-binding protein family. Biometals
Kessler D, Levine L, Fasman G. Some conformational and immunological properties of a bovine brain acidic protein (S-100). Biochemistry
Moore BW. A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun
Heizmann CW, Fritz G, Schäfer BW. S100 proteins: Structure, functions and pathology. Front Biosci
Cicero TJ, Ferrendelli JA, Suntzeff V, Moore BW. Regional changes in CNS levels of the S-100 and 14-3-2 proteins during development and aging of the mouse. J Neurochem
De Vitry F, Picart R, Jacque C, Legault L, Dupouey P, Tixier-Vidal A, et al.
Presumptive common precursor for neuronal and glial cell lineages in mouse hypothalamus. Proc Natl Acad Sci U S A
Herschman HR, Levine L, De Vellis J. Appearance of a brain-specific antigen (S-100 protein) in the developing rat brain. J Neurochem
Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS. Calcium-dependent and -independent interactions of the S100 protein family. Biochem J
Donato R. S100: A multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol
Wolf S, Haase-Kohn C, Pietzsch J. S100A2 in cancerogenesis: A friend or a foe? Amino Acids
Kizawa K, Takahara H, Troxler H, Kleinert P, Mochida U, Heizmann CW, et al.
Specific citrullination causes assembly of a globular S100A3 homotetramer: A putative Ca2+ modulator matures human hair cuticle. J Biol Chem
Ismail TM, Fernig DG, Rudland PS, Terry CJ, Wang G, Barraclough R, et al.
The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis. Carcinogenesis
Hancq S, Salmon I, Brotchi J, De Witte O, Gabius HJ, Heizmann CW, et al.
S100A5: A marker of recurrence in WHO grade I meningiomas. Neuropathol Appl Neurobiol
Leśniak W, Słomnicki ŁP, Filipek A. S100A6 – New facts and features. Biochem Biophys Res Commun
Deol YS, Nasser MW, Yu L, Zou X, Ganju RK. Tumor-suppressive effects of psoriasin (S100A7) are mediated through the β-catenin/T cell factor 4 protein pathway in estrogen receptor-positive breast cancer cells. J Biol Chem
Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, et al.
Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med
Svenningsson P, Greengard P. P11 (S100A10) – An inducible adaptor protein that modulates neuronal functions. Curr Opin Pharmacol
Sakaguchi M, Miyazaki M, Sonegawa H, Kashiwagi M, Ohba M, Kuroki T, et al.
PKCalpha mediates TGFbeta-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11. J Cell Biol
Goyette J, Geczy CL. Inflammation-associated S100 proteins: New mechanisms that regulate function. Amino Acids
Prudovsky I, Donato R. S100a13. UCSD- Nature Molecule Pages
; 2009. Doi: 10.1038/mp.a002115.01
Chen H, Yu D, Luo A, Tan W, Zhang C, Zhao D, et al.
Functional role of S100A14 genetic variants and their association with esophageal squamous cell carcinoma. Cancer Res
Wolf R, Ruzicka T, Yuspa SH. Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: Highly homologous but distinct in regulation and function. Amino Acids
Sturchler E, Cox JA, Durussel I, Weibel M, Heizmann CW. S100A16, a novel calcium-binding protein of the EF-hand superfamily. J Biol Chem
Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al.
S100B's double life: Intracellular regulator and extracellular signal. Biochim Biophys Acta
Luu KC, Nie GY, Salamonsen LA. Endometrial calbindins are critical for embryo implantation: Evidence from in vivo
use of morpholino antisense oligonucleotides. Proc Natl Acad Sci U S A
Austermann J, Nazmi AR, Müller-Tidow C, Gerke V. Characterization of the Ca2+ -regulated ezrin-S100P interaction and its role in tumor cell migration. J Biol Chem
Gribenko AV, Hopper JE, Makhatadze GI. Molecular characterization and tissue distribution of a novel member of the S100 family of EF-hand proteins. Biochemistry
Bresnick AR, Weber DJ, Zimmer DB. S100 proteins in cancer. Nat Rev Cancer
Skelton NJ, Kördel J, Akke M, Forsén S, Chazin WJ. Signal transduction versus buffering activity in Ca2+–binding proteins. Nat Struct Mol Biol
Wang G, Zhang S, Fernig DG, Spiller D, Martin-Fernandez M, Zhang H, et al.
Heterodimeric interaction and interfaces of S100A1 and S100P. Biochem J
Lügering N, Stoll R, Schmid KW, Kucharzik T, Stein H, Burmeister G, et al.
The myeloic related protein MRP8/14 (27E10 antigen) – Usefulness as a potential marker for disease activity in ulcerative colitis and putative biological function. Eur J Clin Invest
Ostendorp T, Leclerc E, Galichet A, Koch M, Demling N, Weigle B, et al.
Structural and functional insights into RAGE activation by multimeric S100B. EMBO J
Kiryushko D, Novitskaya V, Soroka V, Klingelhofer J, Lukanidin E, Berezin V, et al.
Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein. Mol Cell Biol
Leukert N, Vogl T, Strupat K, Reichelt R, Sorg C, Roth J, et al.
Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activity. J Mol Biol
Moroz OV, Antson AA, Dodson EJ, Burrell HJ, Grist SJ, Lloyd RM, et al.
The structure of S100A12 in a hexameric form and its proposed role in receptor signalling. Acta Crystallogr D Biol Crystallogr
Desamero MJ, Delgado RA, de Ocampo GD, Bariuan JV, Collantes TM, Estacio MA. Immunohistochemical demonstration of S100 protein in the ovary of the Philippine water buffalo (Bubalus bubalis
Linnaeus, 1758) (Artiodactyla: Bovidae). Philipp J Vet Med
Nair RR, Khanna A, Singh K. Role of inflammatory proteins S100A8 and S100A9 in pathophysiology of recurrent early pregnancy loss. Placenta
Fritz G, Botelho HM, Morozova-Roche LA, Gomes CM. Natural and amyloid self-assembly of S100 proteins: Structural basis of functional diversity. FEBS J
Abraha HD, Noble PL, Nicolaides KH, Sherwood RA. Maternal serum S100 protein in normal and down syndrome pregnancies. Prenat Diagn
Gazzolo D, Marinoni E, di Iorio R, Lituania M, Bruschettini PL, Michetti F, et al.
Circulating S100beta protein is increased in intrauterine growth-retarded fetuses. Pediatr Res
Morales-Roselló J, Khalil A, Alba-Redondo A, Martinez-Triguero L, Akhoundova F, Perales-Marín A, et al.
Protein S100β in late-pregnancy fetuses with low birth weight and abnormal cerebroplacental ratio. Fetal Diagn Ther
Tskitishvili E, Komoto Y, Temma-Asano K, Hayashi S, Kinugasa Y, Tsubouchi H, et al.
S100B protein expression in the amnion and amniotic fluid in pregnancies complicated by pre-eclampsia. Mol Hum Reprod
Liu AX, Jin F, Zhang WW, Zhou TH, Zhou CY, Yao WM, et al.
Proteomic analysis on the alteration of protein expression in the placental villous tissue of early pregnancy loss. Biol Reprod
Liu XM, Ding GL, Jiang Y, Pan HJ, Zhang D, Wang TT, et al.
Down-regulation of S100A11, a calcium-binding protein, in human endometrium may cause reproductive failure. J Clin Endocrinol Metab
Su NJ, Ma J, Feng DF, Zhou S, Li ZT, Zhou WP, et al.
The peripheral blood transcriptome identifies dysregulation of inflammatory response genes in polycystic ovary syndrome. Gynecol Endocrinol
Hapangama DK, Raju RS, Valentijn AJ, Barraclough D, Hart A, Turner MA, et al.
Aberrant expression of metastasis-inducing proteins in ectopic and matched eutopic endometrium of women with endometriosis: Implications for the pathogenesis of endometriosis. Hum Reprod
Oliva K, Barker G, Rice GE, Bailey MJ, Lappas M. 2D-DIGE to identify proteins associated with gestational diabetes in omental adipose tissue. J Endocrinol
Portela LC, Tort AB, Neto EC, Kessler RG, Penchaszadeh V, Souza DO, et al.
High immunocontent of S100 beta protein in amniotic fluid of pregnancies with down syndrome. Ultrasound Obstet Gynecol
Klein C. Novel equine conceptus-endometrial interactions on day 16 of pregnancy based on RNA sequencing. Reprod Fertil Dev
Bissonnette L, Drissennek L, Antoine Y, Tiers L, Hirtz C, Lehmann S, et al.
Human S100A10 plays a crucial role in the acquisition of the endometrial receptivity phenotype. Cell Adh Migr
Bhagwat SR, Chandrashekar DS, Kakar R, Davuluri S, Bajpai AK, Nayak S, et al.
Endometrial receptivity: A revisit to functional genomics studies on human endometrium and creation of HGEx-ERdb. PLoS One
[Figure 1], [Figure 2]
[Table 1], [Table 2]