Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deciding appropriate therapy for multiple myeloma (MM) is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin (GBT) was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells. We found GBT inhibited cell growth and induced apoptosis with the IC50 values <50 nM. Mechanistic studies using functional approaches identified GBT as an inhibitor of c-Myc. Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. GBT treatment inhibited ERK and AKT signals, while stimulating the activation of JNK cascade. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. The antitumor effect of GBT was validated in a xenograft mouse model and the suppression of MM-induced osteolysis was verified in a SCID-hu model in vivo. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM.
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PMID:Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells. 2689 70

The novel E3 ubiquitin-protein ligase neural precursor cell-expressed developmentally downregulated protein 4 (NEDD4) has been implicated as a crucial factor promoting the tumorigenesis of several types of cancer. The present study investigated the oncogenic role of NEDD4 in hepatocellular carcinoma (HCC) by targeted small interfering RNA silencing of the tumor suppressor phosphatase and tensin homolog (PTEN). Using normal hepatocyte and HCC cell lines, the influence of NEDD4 depletion on proliferation and migration as well as on the PTEN/phosphatidylinositol-3-kinase/protein kinase B signaling pathway was assessed. Additionally, the expression of NEDD4 was assessed in HCC specimens from 78 patients. The in vitro immunohistochemistry results indicated that NEDD4 protein expression was higher, but PTEN expression was lower, in HCC cells compared with normal hepatocytes. The results from the MTT assay, wound healing experiment and Transwell assays demonstrated that NEDD4 depletion lead to decreased proliferation and migration ability of HCC cells. Results from western blotting and immunofluorescence demonstrated that silencing of NEDD4 disrupted the PTEN/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in HCC cells. A total of 55 (70.5%) of the HCC specimens stained positive for NEDD4 and expression significantly correlated with tumor size (P=0.047), differentiation degree (P=0.032), vascular invasion (P<0.001), and lymph node metastasis (P=0.005). Thus, NEDD4 appears to perform a critical role in promoting the proliferation and metastasis of HCC via activation of the PTEN/PI3K/AKT signaling pathway; as such, NEDD4 may be a promising target for novel treatments of HCC.
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PMID:NEDD4 promotes cell growth and migration via PTEN/PI3K/AKT signaling in hepatocellular carcinoma. 2892 9