Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Asthma is a chronic inflammatory condition. Inhibition of the ubiquitin-
proteasome
system offers promise as a anti-inflammatory strategy, being responsible for the degradation of key proteins involved in crucial cellular functions, including gene expression in inflammation (e.g. inhibitory IkappaB-alpha and the endogenous MAPK deactivator - MKP-1). As MKP-1 inhibits MAPK-mediated pro-remodeling functions in human airway smooth muscle (
ASM
; a pivotal immunomodulatory cell in asthma) in this study we investigate the effect of the proteasome inhibitor MG-132 on MKP-1 and evaluate the anti-inflammatory effect of MG-132 on cytokine secretion from
ASM
cells. Examining the time-course of induction of MKP-1 mRNA and protein by MG-132 (10microM) we show that MKP-1 mRNA was first detected at 30min, increased to significant levels by 4h, resulting in a 12.6+/-1.5-fold increase in MKP-1 mRNA expression by 24h (P<0.05). MKP-1 protein levels corroborate the mRNA results. Investigating the effect of MG-132 on secretion of the cytokine IL-6 we show that while short-term pretreatment with MG-132 (30min) partially reduced TNFalpha-induced IL-6 via inhibition of IkappaB-alpha degradation and the NF-kappaB pathway, longer-term
proteasome
inhibition (up to 24h) robustly upregulated MKP-1 and was temporally correlated with repression of p38-mediated IL-6 secretion from
ASM
cells. Moreover, utilizing a cytokine array we show that MG-132 represses the secretion of multiple cytokines implicated in asthma. Taken together, our results demonstrate that MG-132 upregulates MKP-1 and represses cytokine secretion from
ASM
and highlight the potential of the
proteasome
as a therapeutic target in asthma.
...
PMID:Proteasomal inhibition upregulates the endogenous MAPK deactivator MKP-1 in human airway smooth muscle: mechanism of action and effect on cytokine secretion. 2004 58
Ataxia-telangiectasia (AT) and related disorders feature cancer predisposition, neurodegeneration, and immunodeficiency resulting from failure to respond to DNA damage. Hypomorphic mutations in MRE11 cause an AT-like disorder (ATLD) with variable clinical presentation. We have sought to understand how diverse MRE11 mutations may provide unique therapeutic opportunities, and potentially correlate with clinical variability. Here we have undertaken studies of an MRE11 splice site mutation that was found in two ATLD siblings that died of pulmonary adenocarcinoma at the young ages of 9 and 16. The mutation, termed MRE11 alternative splice mutation (MRE11
ASM
), causes skipping of a highly conserved exon while preserving the protein's open reading frame. A new mouse model expressing Mre11
ASM
from the endogenous locus demonstrates that the protein is present at very low levels, a feature in common with the MRE11
ATLD1
mutant found in other patients. However, the mechanisms causing low protein levels are distinct. MRE11
ASM
is mislocalized to the cytoplasm, in contrast to MRE11
ATLD1
, which remains nuclear. Strikingly, MRE11
ASM
mislocalization is corrected by inhibition of the
proteasome
, implying that the protein undergoes strict protein quality control in the nucleus. These findings raise the prospect that inhibition of poorly understood nuclear protein quality control mechanisms might have therapeutic benefit in genetic disorders causing cytoplasmic mislocalization.
...
PMID:Reversible mislocalization of a disease-associated MRE11 splice variant product. 2997 40
