S100B causes apoptosis in a myoblast cell line in a RAGE‐independent manner

Abstract

S100B, a Ca(2+)-modulated protein with both intracellular and extracellular regulatory roles, is most abundant in astrocytes, is expressed in various amounts in several non-nervous cells and is also found in normal serum. Astrocytes secrete S100B, and extracellular S100B exerts trophic and toxic effects on neurons depending on its concentration, in part by interacting with the receptor for advanced glycation end products (RAGE). The presence of S100B in normal serum and elevation of its serum concentration in several non-nervous pathological conditions suggest that S100B-expressing cells outside the brain might release the protein and S100B might affect non-nervous cells. Recently we reported that at picomolar to nanomolar doses S100B inhibits rat L6 myoblast differentiation via inactivation of p38 kinase in a RAGE-independent manner. We show here that at >or=5 nM in the absence of and at >100 nM in the presence of serum S100B causes myoblast apoptosis via stimulation of reactive oxygen species (ROS) production and inhibition of the pro-survival kinase, extracellular signal-regulated kinase (ERK)1/2, again in a RAGE-independent manner. Together with our previous data, the present results suggest that S100B might participate in the regulation of muscle development and regeneration by two independent mechanism, i.e., by inhibiting crucial steps of the myogenic program at the physiological levels found in serum and by causing elevation of ROS production and myoblast apoptosis following accumulation in serum and/or muscle extracellular space. Our data also suggest that RAGE has no role in the transduction of S100B effects on myoblasts, implying that S100B can interact with more than one receptor to affect its target cells.

S100B Expression Modulates Left Ventricular Remodeling After Myocardial Infarction in Mice

“…30 Alternatively, S100B may induce apoptosis in a RAGEindependent manner by interacting with an unidentified receptor, as has been reported in myoblast cell lines via stimulation of reactive oxygen species production and inhibition of the prosurvival kinase ERK1/2. 32 Finally, the present studies do not exclude that the intracellular effects of S100B may themselves modulate the apoptotic response of postinfarct myocytes. In total, S100B expression after infarction may modulate global remodeling by distinct intracellular and extracellular mechanisms that regulate both myocyte growth and apoptosis.…”

Receptor for Advanced Glycation Endproducts Mediates Neutrophil Migration across Intestinal Epithelium

“…However, the involved signaling molecules and their mediated signaling pathways are not clear. In endothelial cells, studies found that ligation of RAGE results in a disruption of the monolayer barrier function (26), leading to increasing endothelial permeability through activation of p38 MAPK (64) and protein kinase C (65). Because in epithelium, RAGE is localized juxtapose to the apical cell junctions, it would be interesting to know whether interactions of RAGE with CD11b/CD18 during PMN transmigration would initiate similar downstream signals that interfere the epithelial junction/barrier functions and thereby open the way for PMN to migrate across.…”

Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes

“…Several studies support the notion that extracellular S100 proteins may have distinct functions in cellular physiology and pathology. For example, S100A4 was reported to stimulate the outgrowth of neurite cells (Novitskaya et al, 2000), whereas S100B has been shown to be involved in the regulation of cell differentiation and survival (Huttunen et al, 2000;Sorci et al, 2003;Sorci et al, 2004a;Sorci et al, 2004b). Another example is S100A12, which has been implicated as an important pro-inflammatory regulator in numerous chronic inflammatory diseases (Foell et al, 2003a;Foell et al, 2003b;Foell et al, 2003c;Foell et al, 2003d).…”

“…Indeed, Roth and co-workers have shown that the S100A12/RAGE interaction plays an important role in the pathology of chronic inflammatory diseases such as bowel disease (Foell et al, 2003c), cystic fibrosis (Foell et al, 2003d), rheumatoid arthritis (Foell et al, 2003b) and vascular disorders (Foell et al, 2003a). Importantly, Donato and colleagues have shown that both RAGE-dependent and -independent extracellular effects of S100B are involved in the regulation of cell survival (Huttunen et al, 2000) and muscle development (Sorci et al, 2003;Sorci et al, 2004a;Sorci et al, 2004b). Although there is no evidence for S100A1 secretion from cardiac cells so far, a release into the extracellular space during myocardial damage has been reported (Kiewitz et al, 2000).…”