Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-induced skeletal muscle wasting involves tumor necrosis factor (TNF) and the ubiquitin-proteasome pathway of muscle protein degradation. In this study, growth of the colon-26 adenocarcinoma in mice was associated with diminished gastrocnemius muscle mass and increased muscle levels of actin, ubiquitin-conjugated proteins, free ubiquitin, E3 ubiquitin ligases, and the type 1 TNF receptor (TNFR1). Indomethacin at 1 or 5 mg/kg/day reduced tumor growth and muscle levels of TNFR1. However, only the 5 mg dose of indomethacin reduced muscle wasting and muscle levels of the E3 ligases and actin. These data suggest that the beneficial effects of indomethacin in the treatment of tumor-induced skeletal muscle wasting may involve inhibition of TNF- and ubiquitin-mediated pathways of muscle protein degradation. These data also demonstrate that E3 ligases, which are involved in disuse atrophy, also are associated with tumor-induced skeletal muscle wasting.
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PMID:Indomethacin preserves muscle mass and reduces levels of E3 ligases and TNF receptor type 1 in the gastrocnemius muscle of tumor-bearing mice. 1562 4

NSAIDs cause severe gastrointestinal injury, in part by suppressing survivin, an inhibitor of apoptosis protein, both in cultured gastric epithelial cells and in human and rat gastric mucosa. The mechanism(s) of survivin down-regulation by NSAIDs is unclear. In this study, we examined whether NSAID treatment decreases survivin mRNA expression and/or enhances degradation of survivin protein via ubiquitin proteasome system in rat gastric mucosal, RGM-1 cells, and whether survivin overexpression prevents indomethacin-induced cell injury and apoptosis. Effects of indomethacin on survivin mRNA expression, survivin protein half-life and ubiquitination were examined in RGM-1 cells. Proteasome inhibitors were utilized to prevent indomethacin-induced survivin protein degradation in RGM-1 cells. The effects of stable overexpression of survivin on indomethacin-induced RGM-1 cell injury and apoptosis were examined. Results showed: (1) Indomethacin treatment did not alter survivin mRNA expression, but significantly reduced survivin protein half-life from 1.5h to approximately 1h and increased survivin ubiquitination. (2) Inhibition of ubiquitin proteasome prolonged survivin protein half-life to over 2h and inhibited indomethacin-induced survivin degradation. (3) Overexpression of survivin significantly reduced indomethacin-induced cell injury and apoptosis. In conclusion, indomethacin treatment enhances degradation of survivin via the ubiquitin proteasome machinery in RGM-1 cells, and maintenance of survivin levels is important for prevention of gastric epithelial cell injury and apoptosis.
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PMID:NSAIDs enhance proteasomic degradation of survivin, a mechanism of gastric epithelial cell injury and apoptosis. 1772 22

Domoic acid (DA) is an excitatory amino acids (EAAs) analog which induced excitotoxicity lesion to central nervous system, but whether induced adult animal spinal cord is not known, furthermore, previous studies have shown that EAAs play an important role in spinal cord lesion, however, the molecular pathways in spinal cord lesion are not fully known. Therefore, a motor neuron-like cell culture system and a DA-induced spinal cord lesioned mice model were used to study the effect of DA on spinal cord in adult mice and the possible molecular pathways of EAAs in spinal cord lesions. Exposure of motor neuron-like cells NSC34 to DA dramatically increased reactive oxygen species (ROS) production by the DCF fluorescent oxidation assay, reduced mitochondrial function by MTT assay, cell viability by trypan blue exclusion assay, and was accompanied by an increase of cell apoptosis by histone protein release assay. In DA-induced spinal cord lesioned mice model, we showed that the decrease of proteasome activity, increase of UCP4 expression by immunohistochemistry and neural cell apoptosis by TUNEL staining, and was accompanied by an decrease of motor disturbance grade during the different stages of DA treatment. Taken together, the in vitro and in vivo data presented in the current report demonstrated that DA induces spinal cord lesions in adult mice, and the multiple molecular pathways promoted by EAAs in spinal cord lesions, at least partially was associated with ROS generation increase, mitochondrial dysfunction, proteasome activity decrease and UCP4 expression increase.
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PMID:Domoic acid induced spinal cord lesions in adult mice: evidence for the possible molecular pathways of excitatory amino acids in spinal cord lesions. 1853 81