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)

Ubiquitin-proteasome pathway (UPP) is the major system for the selective degradation of cellular proteins that play key roles in cellular processes. Previous study indicated that ubiquitin-proteasome inhibitor MG-132 could inhibit growth of some carcinoma. However, anti-carcinoma mechanism of MG-132 is unclear. Our objective was to investigate mechanisms of growth inhibitory effect of MG-132 on gastric carcinoma cells. Gastric carcinoma cell SGC-7901 was treated with ubiquitin-proteasome inhibitor MG-132. Cell growth suppression was evaluated with 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. DNA synthesis was evaluated by (3)H-thymidine ((3)H-TdR) incorporation. Activity of telomerase was examined by telomeric repeat amplification protocol (TRAP) PCR-ELISA. Cell cycle and apoptosis were detected by flow cytometry (FCM). DNA fragment analysis was used to confirm the presence of apoptosis. Expression of p27kip1 and survivin was detected using the western blot method. After exposed to MG-132, the growth and value of (3)H-TdR incorporation of gastric carcinoma cells were obviously inhibited. TRAP PCR-ELISA showed that light absorption of cells gradually decreased after exposed to 5 microM of MG-132 for 24, 48, 72 and 96 h (P < 0.01). The percentage of cells at G(0)/G(1) phase was increased and that at S and G(2)/M phase was decreased (P < 0.01). The ratio of apoptotic cells treated with 5 microM MG-132 for 96 h was 53.7 +/- 6.4%. Agarose electrophoresis showed marked ladders. Moreover, expression of p27kip1 of cells was increased and expression of survivin was decreased. Our results suggest that MG-132 inhibits telomerase activity, induces apoptosis and G(1) arrest which is associated with upregulated p27kip1 expression and downregulated survivin expression in gastric carcinoma cells.
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PMID:MG-132 inhibits telomerase activity, induces apoptosis and G(1) arrest associated with upregulated p27kip1 expression and downregulated survivin expression in gastric carcinoma cells. 1909 61

E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo.
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PMID:E-cadherin destabilization accounts for the pathogenicity of missense mutations in hereditary diffuse gastric cancer. 2247 Apr 75