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)

The tumor suppressor p53 is a short-lived protein that under normal conditions is reduced to a barely detectable level. The stability of p53 protein is primarily regulated in normal non-transformed cells by two interplayers: Mdm2 and p14(ARF). Relocation of p53, Mdm2, and p14(ARF) to the nucleolus seems to regulate, at least partially, the steady-state of p53. Moreover, there are alternative pathways of the regulation of p53 stability in unstressed cells. Jun-N(amino)-terminal kinase (JNK) and poly(ADP-ribose) polymerase-1 (PARP-1) are involved in the regulation of the steady-state of wild-type (wt) p53 protein. However, in most human cervical carcinomas, which express the high-risk human papilloma viruses (HPVs) E6 protein, a complete switch from Mdm2 to HPV E6-mediated degradation of p53 occurs. Virally encoded E6 protein utilizes the cellular ubiquitin-protein ligase termed E6-associated protein (E6-AP) to target p53 protein for proteolytic degradation. We recently addressed the question of whether p53 protein can be generally reactivated by chemotherapy in HeLa cells despite the E6 activity. We observed an increase of cellular p53 after cisplatin (CP) treatment. p53 protein accumulated preferentially in the nucleoli. We checked the cellular level of E6 during CP therapy. Six hours after application of CP the expression of E6 protein was markedly reduced. This coincided with the increase of cellular p53 level and preceded the nucleolar accumulation of p53 protein, thereby indicating that repression of virally coded E6 protein by CP contributes to the restoration of p53 expression.
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PMID:How the nucleolar sequestration of p53 protein or its interplayers contributes to its (re)-activation. 1503 32

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