Neuronal survival activity of S100ββ is enhanced by calcineurin inhibitors and requires activation of NF‐κB

Abstract

S100betabeta is a calcium binding, neurotrophic protein produced by nonneuronal cells in the nervous system. The pathway by which it enhances neuronal survival is unknown. Here we show that S100betabeta enhances survival of embryonic chick forebrain neurons in a dose-dependent manner. In the presence of suboptimal amounts of S100betabeta, neuronal survival is enhanced by the immunosuppressants FK506 and cyclosporin A at concentrations that inhibit calcineurin, which is present in these cells. Rapamycin, an immunosuppressant that does not inhibit calcineurin, did not enhance cell survival. Cypermethrin, a direct and highly specific calcineurin inhibitor, mimicked the immunophilin ligands in its neurotrophic effect. None of the drugs stimulated neuronal survival in the absence of S100betabeta. In the presence of suboptimal amounts of S100betabeta, FK506, cyclosporin A, and cypermethrin (but not rapamycin) also increased NF-kappaB activity, as measured by immunofluorescence of cells stained with antibody to the active subunit (p65) and by immunoblotting of nuclear extracts. Antioxidant and glucocorticoid inhibitors of NF-kappaB decreased both the amount of active NF-kappaB and the survival of neurons caused by S100betabeta alone or in the presence of augmenting drugs. We conclude that S100betabeta enhances the survival of chick embryo forebrain neurons through the activation of NF-kappaB.

S100B Inhibits Myogenic Differentiation and Myotube Formation in a RAGE-Independent Manner

“…The present results are at variance with those obtained with neurons in that neuronal cell lines respond to nanomolar doses of S100B by extending neurites and surviving under stress conditions (3,6,20,21,47) whereas L6 myoblast differentiation and myotube formation are reduced under the same conditions. These differences might reflect differences in intrinsic properties of the two cell systems, likely related to the nature of the receptor that recognizes S100B.…”

“…In the first series of experiments, we analyzed the effects of increasing doses of S100B on myoblast fusion and calculated the myogenic index, i.e., the fraction of nuclei residing in cells containing Ն3 nuclei after staining with MayGrünwald Giemsa, as a measure of myoblast fusion. Upon visual inspection, myotube formation was found to be significantly reduced in the presence of 100 nM S100B (i.e., an S100B concentration that induces neurons to differentiate and astrocytes to proliferate [2,3,6,7,20,21,23,39,47]) and completely blocked in the presence of 5 M S100B (Fig. 1A to C).…”

“…S100B has been shown to interact with neurons, astrocytes, and microglia and to exert various effects on these cells depending on its concentration. S100B has also been shown to enhance neuronal survival and stimulate neurite outgrowth and astrocyte proliferation at nanomolar concentrations (2,3,6,7,16,20,21,23,39,47) and to cause neuronal and astrocyte apoptosis and stimulate interleukin-6 secretion by neurons and nitric oxide release by astrocytes and microglia at micromolar concentrations (1, 18-20, 25, 27, 31). Therefore, S100B has been hypothesized to play roles in brain development and neuronal protection (2,3,6,7,16,20,21,23,39,47) and in the pathophysiology of neurodegenerative disorders (15,20,30,40,41), depending on the concentration attained in the extracellular space.…”

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

“…For example, it increases levels of the beta-amyloid precursor, which in turn may lead to glial activation and formation of amyloid plaques (60). S100B has also been strongly linked to the NF-B pathway and neuronal survival (10). Our results show that S100B is secreted through an ER-Golgi-independent pathway.…”

Estudo da distribuição da proteína S100b em encéfalo de ratos.

“…, amplamente expressa no cérebro e conhecida por promover sobrevivência e diferenciação neuronal através do aumento de cálcio intracelular, regulando a fosforilação de proteínas alvo e a atividade enzimática, translocação do fator nuclear κB (NFκB) e aumentando a expressão da proteína antiapoptótica Bcl-2 (Rothermundt et al, 2003;Alexanian et al, 1999;Castets et al, 1997).…”