Showing papers by "Rosario Donato published in 2007"
TL;DR: Oligomerization of S100 proteins under the non-reducing, high-Ca2+ conditions found extracellularly appears to play a relevant role in RAGE activation, and binding of at least S100A12 and S100B results in RAGES oligomerization.
Abstract: The S100 protein family comprises at least 25 members which, with the exception of S100G, act as Ca2+-sensor proteins that participate in Ca2+ signal transduction by interacting with target proteins thereby modifying their activities. S100 proteins are expressed in vertebrates exclusively, display a cell-specific distribution, and regulate a large variety of intracellular activities. Some S100 proteins are released by a non-classical pathway and exert regulatory effects on several cell types. The receptor for advanced glycation end products (RAGE) has been shown to transduce extracellular effects of S100B, S100A4, S100A6, S100A11, S100A12, S100A13 and S100P. However, some S100 proteins can signal by engaging RAGE as well as non-RAGE receptors. Immune cells (i.e., monocytes/macrophages/microglia, neutrophils and lymphocytes), activated endothelial and vascular smooth muscle cells, neurons, astrocytes, chondrocytes and pancreatic tumor cells are the cell types reported to respond to certain S100 proteins via RAGE engagement. In general, relatively high concentrations of S100 proteins are required for activation of RAGE in responsive cells. S100B is unique in that it can engage RAGE in neurons at low and high concentrations with trophic and toxic effects, respectively, and S100A4 stimulates matrix metalloproteinase 13 release from chondrocytes at nanomolar doses in a RAGE-mediated manner. Oligomerization of S100 proteins under the non-reducing, high-Ca2+ conditions found extracellularly appears to play a relevant role in RAGE activation, and binding of at least S100A12 and S100B results in RAGE oligomerization. Thus, S100/RAGE interactions might have important consequences during development and in tissue homeostasis as well as in inflammatory, degenerative and tumor processes.
268 citations
TL;DR: It is shown here that S100B up‐regulates cyclo‐oxygenase‐2 expression in microglia in a RAGE‐dependent manner in the absence of cofactors through independent stimulation of a Cdc42‐RAC1‐JNK pathway and a Ras‐Rac1‐NF‐κB pathway.
Abstract: Besides exerting regulatory roles within astrocytes, the Ca2+-modulated protein of the EF-hand type S100B is released into the brain extracellular space, thereby affecting astrocytes, neurons, and microglia. However, extracellular effects of S100B vary, depending on the concentration attained and the protein being trophic to neurons up to nanomolar concentrations and causing neuronal apoptosis at micromolar concentrations. Effects of S100B on neurons are transduced by receptor for advanced glycation end products (RAGE). At high concentrations, S100B also up-regulates inducible NO synthase in and stimulates NO release by microglia by synergizing with bacterial endotoxin and IFN-gamma, thereby participating in microglia activation. We show here that S100B up-regulates cyclo-oxygenase-2 expression in microglia in a RAGE-dependent manner in the absence of cofactors through independent stimulation of a Cdc42-Rac1-JNK pathway and a Ras-Rac1-NF-kappaB pathway. Thus, S100B can be viewed as an astrocytic endokine, which might participate in the inflammatory response in the course of brain insults, once liberated into the brain extracellular space.
136 citations
TL;DR: It is shown that deregulation of RAGE expression in myoblasts might concur in rhabdomyosarcomagenesis and that increasing RAGEDeltacyto expression in r HabdomyOSarcoma cells might reduce their tumor potential.
Abstract: Activation of receptor for advanced glycation end products (RAGE) by its ligand, HMGB1, stimulates myogenesis via a Cdc42-Rac1-MKK6-p38 mitogen-activated protein kinase pathway. In addition, functional inactivation of RAGE in myoblasts results in reduced myogenesis, increased proliferation, and tumor formation in vivo. We show here that TE671 rhabdomyosarcoma cells, which do not express RAGE, can be induced to differentiate on transfection with RAGE (TE671/RAGE cells) but not a signaling-deficient RAGE mutant (RAGEΔcyto) (TE671/RAGEΔcyto cells) via activation of a Cdc42-Rac1-MKK6-p38 pathway and that TE671/RAGE cell differentiation depends on RAGE engagement by HMGB1. TE671/RAGE cells also show p38-dependent inactivation of extracellular signal-regulated kinases 1 and 2 and c-Jun NH2 terminal protein kinase and reduced proliferation, migration, and invasiveness and increased apoptosis, volume, and adhesiveness in vitro; they also grow smaller tumors and show a lower tumor incidence in vivo compared with wild-type cells. Two other rhabdomyosarcoma cell lines that express RAGE, CCA and RMZ-RC2, show an inverse relationship between the level of RAGE expression and invasiveness in vitro and exhibit reduced myogenic potential and enhanced invasive properties in vitro when transfected with RAGEΔcyto. The rhabdomyosarcoma cell lines used here and C2C12 myoblasts express and release HMGB1, which activates RAGE in an autocrine manner. These data suggest that deregulation of RAGE expression in myoblasts might concur in rhabdomyosarcomagenesis and that increasing RAGE expression in rhabdomyosarcoma cells might reduce their tumor potential.
63 citations