Extracellular S100B protein modulates ERK in astrocyte cultures

Gonçalves, Daniela; Lenz, Guido; Karl, Juliana Damm; Gonçalves, Carlos Alberto; Rodnight, Richard

doi:10.1097/00001756-200003200-00030

Cited by 63 publications

(39 citation statements)

References 3 publications

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“…A growth factor for glial cells, S100B, 17) which is another member of the S100 family, weakly increased the activity of ERK. 18) These results suggested that ERK was not the main signaling pathway for the growth-stimulating activity of S100A9, but may be involved in the signaling pathway.…”

Section: Discussionmentioning

confidence: 89%

Mitogenic Activity of S100A9 (MRP-14)

Shibata

Ito

Ohkuma

et al. 2005

Biological & Pharmaceutical Bulletin

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S100A9 is a calcium binding protein found in high amounts in granulocytes and monocytes. We have shown that S100A9 stimulated the proliferation of fibroblasts, but its mechanism remains unknown. In this report, S100A9 is shown to be mitogenic and to stimulate fibroblast proliferation without other growth factors in the serum. Although an S100A8/S100A9 heteropolymer inhibited the growth of fibroblasts by chelating zinc ions, these ions had no effect on the growth-stimulating activity of S100A9. The effects of serum and S100A9 on fibroblast growth were additive, and S100A9 stimulated the growth without serum. Furthermore, S100A9 stimulated the incorporation of bromodeoxyuridine in fibroblasts. However, the effect of S100A9 on the activation of extracellular signal regulated protein kinases (ERK) was small. These results suggest that S100A9 is involved in the regulation of inflammatory processes by modulating fibroblast proliferation.

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Section: Discussionmentioning

confidence: 89%

Mitogenic Activity of S100A9 (MRP-14)

Shibata

Ito

Ohkuma

et al. 2005

Biological & Pharmaceutical Bulletin

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“…It has been long known that S100B has to be in its disulfide crosslinked dimer conformation to exert trophic effects on neurons and that the presence of both Cys 68 and Cys 84 in each S100B monomer is essential to the neurotrophic effects of the protein (15). However, recent observations indicate that: (i) S100A12, the human analogue of EN-RAGE, which activates inflammatory cells (4), does not contain Cys residues; (ii) a mutant of S100B lacking the last nine residues (and hence Cys 84 ) stimulates nitric oxide production and secretion by astrocytes (50); and (iii) oxidized and non-oxidized S100B cause an identical activation of ERK1/ERK2 in astrocytes at concentrations higher than 10 nM (24). Thus, the S100B effects described here seem to be independent of the oxidation state of S100B, and interaction of S100 proteins with RAGE does not require the previous formation of disulfide cross-linked dimers.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, nanomolar concentrations of extracellular S100B have been shown to enhance neuronal survival and neurite outgrowth via nuclear translocation of NF-B (23) and to increase the activity of extracellular signal-regulated kinases (ERK) in astrocytes (24). These findings strongly suggest that ).…”

mentioning

confidence: 99%

Coregulation of Neurite Outgrowth and Cell Survival by Amphoterin and S100 Proteins through Receptor for Advanced Glycation End Products (RAGE) Activation

Huttunen¹,

Kuja-Panula²,

Sorci³

et al. 2000

Journal of Biological Chemistry

541

532

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Amphoterin is a protein enhancing process extension and migration in embryonic neurons and in tumor cells through binding to receptor for advanced glycation end products (RAGE), a multiligand transmembrane receptor. S100 proteins, especially S100B, are abundantly expressed in the nervous system and are suggested to function as cytokines with both neurotrophic and neurotoxic effects. However, the cell surface receptor for the cytokine function of S100B has not been identified. Here we show that two S100 family proteins, S100B and S100A1, activate RAGE in concert with amphoterin inducing neurite outgrowth and activation of transcription factor NF-B. Furthermore, activation of RAGE by amphoterin and S100B promotes cell survival through increased expression of the anti-apoptotic protein Bcl-2. However, whereas nanomolar concentrations of S100B induce trophic effects in RAGE-expressing cells, micromolar concentrations of S100B induce apoptosis in an oxidant-dependent manner. Both trophic and toxic effects are specific for cells expressing full-length RAGE since cells expressing a cytoplasmic domain deletion mutant of RAGE are unresponsive to these stimuli. These findings suggest that activation of RAGE by multiple ligands is able to promote trophic effects whereas hyperactivation of RAGE signaling pathways promotes apoptosis. We suggest that RAGE is a signal-transducing receptor for both trophic and toxic effects of S100B.Receptor for advanced glycation end products (RAGE) 1 is a member of the immunoglobulin superfamily of cell surface proteins interacting with a range of ligands, including advanced glycation end products (AGE) (1), amyloid-␤ peptide (2), amphoterin (3), and members of the S100 family (4). Whereas AGE and amyloid-␤ peptide are known to induce cellular perturbation through their interaction with RAGE, amphoterin and S100 proteins are considered to be physiological ligands of RAGE in migratory and inflammatory cellular responses. However, mechanistically it is not understood how RAGE-mediated cellular responses can change from trophic to toxic.Amphoterin is a heparin-binding, neurite outgrowth-promoting protein that is highly expressed in embryonic and transformed cells (5-7). RAGE has been shown to mediate neurite outgrowth of cortical neurons and neuroblastoma cells on amphoterin-coated substrates (3, 8). Furthermore, amphoterin and RAGE co-localize at the leading edge of advancing neurites in the developing central nervous system (3). Our previous results suggesting that amphoterin might be a more general regulator of cell migration (reviewed in Ref. 9) are supported by the recent findings showing that blockade of amphoterin-RAGE interaction decreases invasion and growth of both implanted and spontaneously developing tumors (10). S100B is a member of a multigenic family of Ca 2ϩ -regulated proteins of the EF-hand type that has been implicated in the regulation of protein phosphorylation, the dynamics of cytoskeleton constituents, the cell cycle, and some enzymes (11,12). S100B is abundant in the n...

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“…Similarly, interaction of S100B with p53 was shown to inhibit protein kinase C phosphorylation (6,7). When secreted by astrocytes, in addition to an autocrine effect leading, for example, to the activation of extracellular signal-regulated kinase (8), S100B can have a paracrine effect on neurons, promoting their survival during development and after injury through the NF-B pathway, as well as through neurite outgrowth (1, 9 -11). However, the extracellular concentration of S100B plays a crucial role in the physiological response.…”

Section: Treatment Of Cells With Tpen (Nnnn-tetrakis(2-pyridylmethmentioning

confidence: 99%

Intracellular Ca2+ and Zn2+ Levels Regulate the Alternative Cell Density-dependent Secretion of S100B in Human Glioblastoma Cells

Davey

Murmann

Heizmann

2001

Journal of Biological Chemistry

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In recent years, protein translocation has been implicated as the mechanism that controls assembly of signaling complexes and induction of signaling cascades. Several members of the multifunctional Ca 2؉ -(Zn 2؉ -and Cu 2؉ )-binding S100 proteins appear to translocate upon cellular stimulation, and some are even secreted from cells, exerting extracellular functions. We transfected cells with S100B-green fluorescent fusion proteins and followed the relocation in real time. A small number of cells underwent translocation spontaneously. However, the addition of thapsigargin, which increases Ca 2؉ levels, intensified ongoing translocation and secretion or induced these processes in resting cells. On the other hand, EGTA or BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid), the Ca 2؉ -chelating agents, inhibited these processes. In contrast, relocation of S100B seemed to be negatively dependent on Zn 2؉ levels. Treatment of cells with TPEN (N,N,N,N-tetrakis(2-pyridylmethyl)ethylenediamine), a Zn 2؉ -binding drug, resulted in a dramatic redistribution and translocation of S100B. Secretion of S100B, when measured by ELISA, was dependent on cell density. As cells reached confluence the secretion drastically declined. However, an increase in Ca 2؉ levels, and even more so, a decrease in Zn 2؉ concentration, reactivated secretion of S100B. On the other hand, secretion did not decrease by treatment with brefeldin A, supporting the view that this process is independent of the endoplasmic reticulum-Golgi classical secretion pathway. S100B is a small acidic protein containing two distinct EFhands, predominantly expressed in astrocytes, oligodendrocytes, and Schwann cells. Intracellularly, S100B regulates the cytoskeletal dynamics through disassembly of tubulin filaments and binding to fibrillary proteins such as CapZ (1-4). Furthermore, S100B interacts in a Ca 2ϩ -dependent manner with the cytoplasmic domain of myelin-associated glycoprotein and inhibits its phosphorylation by protein kinase A (5). Similarly, interaction of S100B with p53 was shown to inhibit protein kinase C phosphorylation (6, 7). When secreted by astrocytes, in addition to an autocrine effect leading, for example, to the activation of extracellular signal-regulated kinase (8), S100B can have a paracrine effect on neurons, promoting their survival during development and after injury through the NF-B pathway, as well as through neurite outgrowth (1, 9 -11). However, the extracellular concentration of S100B plays a crucial role in the physiological response. Although nanomolar quantities have trophic effects on cells, high levels of this protein have been implicated in glial activation (a prominent feature in Down syndrome and Alzheimer's disease), up-regulation of nitric-oxide synthase, and apoptosis (11-13). Recently, Schmidt and colleagues (14, 15) identified the surface receptor RAGE (receptor for advanced glycation endproducts) for S100B, shedding more light on its extracellular function. Others also demonstrated that the binding of extracel...

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Extracellular S100B protein modulates ERK in astrocyte cultures

Cited by 63 publications

References 3 publications

Mitogenic Activity of S100A9 (MRP-14)

Mitogenic Activity of S100A9 (MRP-14)

Coregulation of Neurite Outgrowth and Cell Survival by Amphoterin and S100 Proteins through Receptor for Advanced Glycation End Products (RAGE) Activation

Intracellular Ca2+ and Zn2+ Levels Regulate the Alternative Cell Density-dependent Secretion of S100B in Human Glioblastoma Cells

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