Biomolecules

Editorial

Jump to: Research, Review

5 pages, 176 KiB

Open AccessEditorial

S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology

by Wiesława Leśniak and Anna Filipek

Biomolecules 2024, 14(4), 432; https://doi.org/10.3390/biom14040432 - 02 Apr 2024

Viewed by 476

Abstract

The S100 proteins are small, ubiquitous, mostly homodimeric proteins containing two EF-hand structures, that is, helix-loop-helix motifs specialized in high-affinity calcium-binding (~10⁻⁶ M) [...] Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

Research

Jump to: Editorial, Review

13 pages, 2326 KiB

Open AccessArticle

Differential Expression of Circulating Damage-Associated Molecular Patterns in Patients with Coronary Artery Ectasia

by James N. Tsoporis, Andreas S. Triantafyllis, Andreas S. Kalogeropoulos, Shehla Izhar, Angelos G. Rigopoulos, Loukianos S. Rallidis, Eleftherios Sakadakis, Ioannis K. Toumpoulis, Vasileios Salpeas, Howard Leong-Poi, Thomas G. Parker and Ioannis Rizos

Biomolecules 2024, 14(1), 10; https://doi.org/10.3390/biom14010010 (registering DOI) - 21 Dec 2023

Viewed by 975

Abstract

Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. [...] Read more.

Coronary artery ectasia (CAE) is defined as abnormal dilation of a coronary artery with a diameter exceeding that of adjacent normal arterial segment by >1.5 times. CAE is a pathological entity of the coronary arteries and characterized as a variant of coronary atherosclerosis. CAE frequently coexists with coronary artery disease (CAD). While inflammation appears to be involved, the pathophysiology of CAE remains unclear. Damage-associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue, are deemed as alarm signals by the innate immune system. Inflammatory agents can generate DAMPs and DAMPs can create a pro-inflammatory state. In a prospective cross-sectional study, we enrolled 29 patients with CAE and non-obstructive CAD, 19 patients with obstructive CAD without CAE, and 14 control subjects with normal (control) coronary arteries age- and sex-matched with the CAE patients, to investigate the differential expression of plasma DAMPs. Patients with CAE and non-obstructive CAD had increased plasma levels of the DAMPs S100B, S100A12, HMGB1, and HSP70, the DAMPs receptor TLR4, and miR328a-3p compared to CAD and controls. Plasma levels of the mir328a-3p target the protective soluble form of the DAMPs receptor for advanced glycation end products (sRAGE), and the antioxidant DJ-1 was decreased in both CAE and CAD compared to controls. In an in vitro human umbilical vein endothelial cells model, circulating levels of S100B, HMGB1, HSP70 as well as CAE patient plasma induced inflammatory responses. The differential expression of the DAMPs S100B, HSP70, HMGB1, and their receptors TLR4 and sRAGE in CAE versus CAD makes them attractive novel biomarkers as therapeutic targets and therapeutics. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

24 pages, 13058 KiB

Open AccessArticle

Interaction of S100A6 Protein with the Four-Helical Cytokines

by Alexey S. Kazakov, Evgenia I. Deryusheva, Victoria A. Rastrygina, Andrey S. Sokolov, Maria E. Permyakova, Ekaterina A. Litus, Vladimir N. Uversky, Eugene A. Permyakov and Sergei E. Permyakov

Biomolecules 2023, 13(9), 1345; https://doi.org/10.3390/biom13091345 - 04 Sep 2023

Cited by 2 | Viewed by 1114

Abstract

S100 is a family of over 20 structurally homologous, but functionally diverse regulatory (calcium/zinc)-binding proteins of vertebrates. The involvement of S100 proteins in numerous vital (patho)physiological processes is mediated by their interaction with various (intra/extra)cellular protein partners, including cell surface receptors. Furthermore, recent [...] Read more.

S100 is a family of over 20 structurally homologous, but functionally diverse regulatory (calcium/zinc)-binding proteins of vertebrates. The involvement of S100 proteins in numerous vital (patho)physiological processes is mediated by their interaction with various (intra/extra)cellular protein partners, including cell surface receptors. Furthermore, recent studies have revealed the ability of specific S100 proteins to modulate cell signaling via direct interaction with cytokines. Previously, we revealed the binding of ca. 71% of the four-helical cytokines via the S100P protein, due to the presence in its molecule of a cytokine-binding site overlapping with the binding site for the S100P receptor. Here, we show that another S100 protein, S100A6 (that has a pairwise sequence identity with S100P of 35%), specifically binds numerous four-helical cytokines. We have studied the affinity of the recombinant forms of 35 human four-helical cytokines from all structural families of this fold to Ca²⁺-loaded recombinant human S100A6, using surface plasmon resonance spectroscopy. S100A6 recognizes 26 of the cytokines from all families of this fold, with equilibrium dissociation constants from 0.3 nM to 12 µM. Overall, S100A6 interacts with ca. 73% of the four-helical cytokines studied to date, with a selectivity equivalent to that for the S100P protein, with the differences limited to the binding of interleukin-2 and oncostatin M. The molecular docking study evidences the presence in the S100A6 molecule of a cytokine-binding site, analogous to that found in S100P. The findings argue the presence in some of the promiscuous members of the S100 family of a site specific to a wide range of four-helical cytokines. This unique feature of the S100 proteins potentially allows them to modulate the activity of the numerous four-helical cytokines in the disorders accompanied by an excessive release of the cytokines. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

22 pages, 4953 KiB

Open AccessFeature PaperArticle

An Extracellular/Membrane-Bound S100P Pool Regulates Motility and Invasion of Human Extravillous Trophoblast Lines and Primary Cells

by Tara Lancaster, Maral E. A. Tabrizi, Mariaelena Repici, Janesh Gupta and Stephane R. Gross

Biomolecules 2023, 13(8), 1231; https://doi.org/10.3390/biom13081231 - 09 Aug 2023

Viewed by 1070

Abstract

Whilst S100P has been shown to be a marker for carcinogenesis, we have shown, in non-physio-pathological states, that its expression promotes trophoblast motility and invasion but the mechanisms explaining these cellular processes are unknown. Here we identify the presence of S100P in the [...] Read more.

Whilst S100P has been shown to be a marker for carcinogenesis, we have shown, in non-physio-pathological states, that its expression promotes trophoblast motility and invasion but the mechanisms explaining these cellular processes are unknown. Here we identify the presence of S100P in the plasma membrane/cell surface of all trophoblast cells tested, whether lines, primary extravillous (EVT) cells, or section tissue samples using either biochemical purification of plasma membrane material, cell surface protein isolation through biotinylation, or microscopy analysis. Using extracellular loss of function studies, through addition of a specific S100P antibody, our work shows that inhibiting the cell surface/membrane-bound or extracellular S100P pools significantly reduces, but importantly only in part, both cell motility and cellular invasion in different trophoblastic cell lines, as well as primary EVTs. Interestingly, this loss in cellular motility/invasion did not result in changes to the overall actin organisation and focal adhesion complexes. These findings shed new light on at least two newly characterized pathways by which S100P promotes trophoblast cellular motility and invasion. One where cellular S100P levels involve the remodelling of focal adhesions whilst another, an extracellular pathway, appears to be focal adhesion independent. Both pathways could lead to the identification of novel targets that may explain why significant numbers of confirmed human pregnancies suffer complications through poor placental implantation. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

16 pages, 311 KiB

Open AccessArticle

S100s and HMGB1 Crosstalk in Pancreatic Cancer Tumors

by Angelo Mandarino, Swetha Thiyagarajan, Allana C. F. Martins, Roberto da Silva Gomes, Stefan W. Vetter and Estelle Leclerc

Biomolecules 2023, 13(8), 1175; https://doi.org/10.3390/biom13081175 - 28 Jul 2023

Viewed by 1123

Abstract

Pancreatic cancer remains a disease that is very difficult to treat. S100 proteins are small calcium binding proteins with diverse intra- and extracellular functions that modulate different aspects of tumorigenesis, including tumor growth and metastasis. High mobility group box 1 (HMGB1) protein is [...] Read more.

Pancreatic cancer remains a disease that is very difficult to treat. S100 proteins are small calcium binding proteins with diverse intra- and extracellular functions that modulate different aspects of tumorigenesis, including tumor growth and metastasis. High mobility group box 1 (HMGB1) protein is a multifaceted protein that also actively influences the development and progression of tumors. In this study, we investigate the possible correlations, at the transcript level, between S100s and HMGB1 in pancreatic cancer. For this purpose, we calculated Pearson’s correlations between the transcript levels of 13 cancer-related S100 genes and HMGB1 in a cDNA array containing 19 pancreatic cancer tumor samples, and in 8 human pancreatic cancer cell lines. Statistically significant positive correlations were found in 5.5% (5 out of 91) and 37.4% (34 of 91) of the possible S100/S100 or S100/HMGB1 pairs in cells and tumors, respectively. Our data suggest that many S100 proteins crosstalk in pancreatic tumors either with other members of the S100 family, or with HMGB1. These newly observed interdependencies may be used to further the characterization of pancreatic tumors based on S100 and HMGB1 transcription profiles. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

19 pages, 2385 KiB

Open AccessArticle

Targeted Destruction of S100A4 Inhibits Metastasis of Triple Negative Breast Cancer Cells

by Thamir M. Ismail, Rachel G. Crick, Min Du, Uma Shivkumar, Andrew Carnell, Roger Barraclough, Guozheng Wang, Zhenxing Cheng, Weiping Yu, Angela Platt-Higgins, Gemma Nixon and Philip S. Rudland

Biomolecules 2023, 13(7), 1099; https://doi.org/10.3390/biom13071099 - 10 Jul 2023

Cited by 1 | Viewed by 8818

Abstract

Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of [...] Read more.

Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC₅₀, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC₅₀, 8 nM) and human TNBC (IC₅₀, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC₅₀, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10–100 nM concentration range (Fisher’s Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

11 pages, 960 KiB

Open AccessArticle

Emergent Inflammatory Markers and Echocardiographic Indices in Patients with Bronchial Asthma

by Nikolaos A. Gkavogiannakis, James N. Tsoporis, Ioannis-Alexandros Drosatos, George Tsirebolos, Shehla Izhar, Eleftherios Sakadakis, Andreas S. Triantafyllis, Thomas G. Parker, Lampros A. Kalogiros, Howard Leong-Poi, Loukianos S. Rallidis and Ioannis Rizos

Biomolecules 2023, 13(6), 955; https://doi.org/10.3390/biom13060955 - 07 Jun 2023

Cited by 1 | Viewed by 1289

Abstract

Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein [...] Read more.

Asthma is a heterogeneous disease, characterized by chronic inflammation and oxidative stress of the airways. Several inflammatory pathways including activation of the receptor for advanced glycation end products (RAGE) have been described in the course of the disease. DJ-1 is a redox-sensitive protein with multifaceted roles in mast cell homeostasis and an emerging role in the pathogenesis of asthma. Moreover, cardiac function abnormalities have been described via echocardiography in patients with asthma. The main aim of this study was to investigate the plasma levels of RAGE, its ligands and DJ-1 in asthmatic patients pre- and post-treatment along with echocardiographic indices of cardiovascular function. The study population was divided into two groups. Group A included 13 patients with newly diagnosed bronchial asthma who were free of treatment for at least two weeks and Group B included 12 patients without asthma. An echocardiography examination was performed on all patients. The plasma levels of RAGE, its ligands (AGEs, S100A12, S100B, S100A8/A9), the interleukins (IL-6, IL-1β) and DJ-1 were measured. No differences were noted among the two groups for baseline characteristics and echocardiographic indices of cardiac function. In Group A, 31% suffered from mild asthma, 54% from moderate asthma and 15% from severe asthma. Plasma levels of IL-6, AGEs and AGE/RAGE ratio were increased and those of S100A12 and DJ-1 were decreased in asthmatics. Pharmacotherapy with corticosteroids/β2-agonists decreased IL-6, and AGEs, and increased DJ-1. In search of novel approaches in diagnosing and treating patients with asthma, S100A12, ratio AGE/sRAGE, and DJ-1 in addition to IL-6 may prove to be useful tools. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

32 pages, 3082 KiB

Open AccessReview

Recent Advances in Molecular and Cellular Functions of S100A10

by Gillian C. Okura, Alamelu G. Bharadwaj and David M. Waisman

Biomolecules 2023, 13(10), 1450; https://doi.org/10.3390/biom13101450 - 26 Sep 2023

Viewed by 1551

Abstract

S100A10 (p11, annexin II light chain, calpactin light chain) is a multifunctional protein with a wide range of physiological activity. S100A10 is unique among the S100 family members of proteins since it does not bind to Ca²⁺, despite its sequence and [...] Read more.

S100A10 (p11, annexin II light chain, calpactin light chain) is a multifunctional protein with a wide range of physiological activity. S100A10 is unique among the S100 family members of proteins since it does not bind to Ca²⁺, despite its sequence and structural similarity. This review focuses on studies highlighting the structure, regulation, and binding partners of S100A10. The binding partners of S100A10 were collated and summarized. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

12 pages, 1833 KiB

Open AccessReview

An Update on S100A16 in Human Cancer

by Suyog Basnet, Evan Michael Vallenari, Urusha Maharjan, Sunita Sharma, Olaf Schreurs and Dipak Sapkota

Biomolecules 2023, 13(7), 1070; https://doi.org/10.3390/biom13071070 - 03 Jul 2023

Cited by 1 | Viewed by 2317

Abstract

S100A16 is a member of the S100 protein family. S100A16 is expressed in a variety of human tissues, although at varying levels. S100A16 expression is especially high in tissues rich in epithelial cells. mRNA and protein levels of S100A16 have been reported to [...] Read more.

S100A16 is a member of the S100 protein family. S100A16 is expressed in a variety of human tissues, although at varying levels. S100A16 expression is especially high in tissues rich in epithelial cells. mRNA and protein levels of S100A16 have been reported to be differentially expressed in the majority of human cancers. Functionally, S100A16 has been linked to several aspects of tumorigenesis, for example, cell proliferation, differentiation, migration, invasion, and epithelial-mesenchymal transition (EMT). Accordingly, S100A16 has been suggested to have both tumour-promoting and suppressive roles in human cancers. S100A16-mediated cellular functions are suggested to be mediated by the regulation of various signaling pathways/proteins including EMT-related proteins E-cadherin and Vimentin, PI3K-AKT, p53, MMP1-1, MMP-2, MMP-9, JNK/p38, etc. In addition to the functional roles, expression of S100A16 has been suggested to have prognostic potential in various cancer types. The aims of this review are to summarise the expression profile, identify common molecular partners and functional roles, and explore the prognostic potential of S100A16 in human cancers. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0)

► Show Figures

Figure 1

Journal Menu

Journal Browser

S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology 2.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Related Special Issues

Published Papers (9 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI