Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of small airway epithelial (SAEC) cells or lung epithelial (Beas2B) cells with TNF-alpha or PMA induces urokinase-type plasminogen activator (uPA) expression. Treatment of these cells with TNF-alpha, PMA or cycloheximide but not TGF-beta increased steady-state expression of uPAmRNA. TNF-alpha, PMA or cycloheximide caused 8-10 fold extensions of the uPAmRNA half-life in SAEC or Beas2B cells treated with DRB, a transcriptional inhibitor. These findings suggest that uPA gene expression involves a post-transcriptional regulatory mechanism. Using gel mobility shift and UV cross-linking assays, we identified a 30 kDa uPA mRNA binding protein (uPA mRNABp) that selectively binds to a 66 nt protein binding fragment of uPA mRNA containing regulatory information for message stabilization. Binding of cytoplasmic uPA mRNABp to uPA mRNA was abolished after treatment with TNF-alpha but not TGF-beta. In addition, we found the accumulation of 30 kDa uPAmRNABp in the nuclear extracts of TNF-alpha but not TGF-beta treated cells. The uPA mRNABp starts moving to the nucleus from the cytoplasmic compartment as early as three hours after TNF-alpha treatment. Complete translocation is achieved between 12-24 h, which coincides with the maximal expression of uPA protein effected by cytokine stimulation. Treatment of Beas2B cells with NaF inhibited TNF-alpha-mediated translocation of uPA mRNABp from the cytoplasm to the nucleus and concomitant inhibition of uPA expression. TNF-alpha stabilizes uPA mRNA by translocating the uPA mRNABp from the cytoplasm to the nucleus. Our results demonstrate a novel mechanism governing uPA mRNA stability through shuttling of uPA mRNABp between the nucleus and cytoplasm. This newly identified pathway may have evolved to regulate uPA-mediated functions of the lung epithelium in inflamation or neoplasia.
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PMID:Cytoplasmic-nuclear shuttling of the urokinase mRNA binding protein regulates message stability. 1223 87

Expression of the urokinase-type plasminogen activator (uPA) is under tight regulation by hormones, cytokines and growth factors under physiological conditions. Treatment of lung epithelial (Beas2B) cells with translation inhibitors induces uPA mRNA expression, as well as early response genes. To understand the specific expression and regulation of uPA mRNA, we treated Beas2B cells with cycloheximide (CycD), anisomycin, emitine and puromycin in a time-dependent manner and measured uPA mRNA expression by Northern blotting. All these agents induced uPA mRNA by two- to seven-fold within 3 h after treatment in Beas2B cells. CycD, emitine, puromycin and anisomycin also enhanced uPA mRNA half-life by three- to five-fold in Beas2B cells treated with DRB, an inhibitor of transcription. However, run-on-transcription experiments indicated that these agents failed to induce uPA mRNA transcription indicating that they augment uPA mRNA mainly due to increased stability. Using gel mobility shift, we identified an uPA mRNA binding protein (uPA mRNABp) that selectively binds to uPA mRNA [Gyetko MR, Todd III RF, Wilkinson CC, Sitrin RG: The urokinase receptor is required for human monocyte chemotaxis in vitro. J Clin Invest 93: 1380-1387, 1994]. Binding of both cytoplasmic and nuclear uPA mRNABp to uPA mRNA was abolished after treatment with translation inhibitors, which coincides with the maximal expression of uPA mRNA. We also found a similar decline in HuR and heterogeneous nuclear ribonucleoprotein C (hnRNPC) which are known to stabilize uPA mRNA both in the nuclear and cytosolic compartments. These results strongly suggest that increased uPA mRNA stability induced by translational inhibitors involves the interaction of uPA mRNA with a degrading protein factor rather than increased interaction of proteins that are known to stabilize uPA mRNA. These data also strongly suggests that down-regulation of the uPA-uPA mRNABp interaction by translational inhibitors rather than the translocation of uPA mRNABp contributes to increased uPA mRNA stability. This pathway may regulate uPA-mediated functions of the lung epithelium in the context of inflammation or neoplasia.
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PMID:Protein synthesis and urokinase mRNA metabolism. 1588 51