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)

Epithelial ovarian cancer (EOC) has a very poor prognosis because of tumor invasiveness. Here, we reported that SET and MYND domain containing protein 3 (SMYD3), a lysine methyltransferase, was frequently upregulated in EOC and associated with poor prognosis. A series of in vitro assays demonstrated that SMYD3 significantly upgraded the migration ability of EOC cells. The results of in vivo EOC metastasis models further confirmed that overexpression of SMYD3 promoted EOC progression. Mechanistic investigations indicated that SMYD3 cloud decrease p53 protein stability and induce epithelial-mesenchymal transition in EOC cells. SMYD3 interacts with p53 directly via the post-SET domain and destabilizes p53 by inducing p53 translocation from the nucleus to the cytoplasm and promoting p53 ubiquitination modification independent of MDM2. Furthermore, the mass spectrometry results showed that SMYD3 interacts with UBE2R2, an ubiquitin-conjugating enzyme (E2) of the ubiquitin-proteasome pathway. The combination of UBE2R2-SMYD3-p53 significantly promotes the ubiquitination and degradation of p53. These results pointed that SMYD3 might be a new E3 ligase of p53. Further analysis confirmed that lysines 381, 382 and 386 of p53 are the key sites for the ubiquitination modification of SMYD3 to p53. In summary, our results define the important role of SMYD3 in the metastasis process of EOC and present a new therapeutic target against EOC.
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PMID:SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination. 3100 12

The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure-function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.
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PMID:Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases. 3245 57