Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cysteine-rich 61 (Cyr61) belongs to the CCN family and mediates cell proliferation, survival, and apoptosis. Our previous studies showed that Cyr61 protected against hyperoxia-induced lung cell death via Akt phosphorylation. Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. Emerging data show that cav-1 regulates signal transduction-associated proteins that reside in the caveolae. Numerous integrin-related pathways, including PI3K/Akt-induced cell survival are controlled by cav-1-mediated signaling. Our data showed that recombinant Cyr61 promoted cell proliferation and resistance to hyperoxia-induced cell death in vitro. Neutralizing antibodies reversed the above effects, indicating functional role of secreted Cyr61 in response to hyperoxic stress. While deletion of cav-1 protected cells from hyperoxia-induced cell death, Cyr61-neutralizing antibodies abolished this protective effect. Furthermore, Cyr61 and cav-1 colocalized and physically interacted via integrins in bronchial epithelial cells. Deletion of cav-1 increased extracellular and decreased cytosolic Cyr61, both in vitro and in vivo. Pretreatment with Brefeldin A increased intracellular Cyr61 in cav-1(-/-) cells, while decreasing extracellular Cyr61. Taken together, Cav-1/Cyr61 interaction via integrins represents a novel pathway of Cyr61 signaling involving cav-1-dependent processes, which play a critical role in regulating hyperoxia-induced cell death.
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PMID:Caveolin-1 regulates the secretion and cytoprotection of Cyr61 in hyperoxic cell death. 1880 24

Signal transduction by the Toll-like receptors (TLRs) is a key component of innate immunity against many pathogens and also underlies a large burden of human diseases. Therefore, the mechanisms and regulation of signaling from the TLRs are of considerable interest. Here we seek to determine the molecular mechanism by which TLR2 and TLR4, members of the Toll-like receptor family, are activated by bacterial LPS, hyperoxia, and zymosan respectively. Our central hypothesis is that the oxidation state of cysteine thiols on the ectodomain of TLR2 and TLR4 are critical for pathogen-initiated intracellular signaling as well in hyperoxia. Cysteine thiols of TLR4 and its co-receptor MD2 have been shown to aid binding between the two molecules and also bacterial LPS binding to the receptor complex. We extend these findings by demonstrating the oxidation of free thiols on the ectodomain of hTLR4, after exposure to LPS or hyperoxia suggesting that the cysteines on the ectodomain of TLR4 could form intra- or intermolecular disulfide bonds. We also demonstrated blockade of intracellular signaling from TLR4 and TLR2 by thiol-modifying compounds which suggest a novel therapeutic intervention for sepsis, hyperoxia-induced cell injury and yeast infection. In these experiments CHO-3E10, HEK293 cells expressing hTLR2 or hTLR4 and mouse peritoneal macrophages cells were pretreated with cell impermeable maleimides to alkylate thiols on the extracellular domain of TLRs, cells were then exposed to LPS, hyperoxia or zymosan. In all of these models, we detected decreased intracellular signaling from TLR2 or TLR4. Furthermore, incubation with phenyl arsine oxide - which forms stable complexes with vicinal cysteine residues - prevented LPS induced HEK293/hTLR4 intracellular signaling which was reversed by DMPS. Sequence analysis of different TLRs revealed Leucine-Rich Repeat C-terminal (LRRCT) domain that contains 4 conserved cysteines. Further work is required to pinpoint the role of each cysteine in receptor dimerization, pathogen binding, hyperoxia modulation, and intracellular signaling.
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PMID:The oxidation state of cysteine thiols on the ectodomain of TLR2 and TLR4 influences intracellular signaling. 3184 60