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)

Dysregulation of the ubiquitin-proteasome pathway is closely associated with cancer initiation and progression. SPOP is an adapter protein of the CUL3-based E3 ubiquitin ligase complexes. Several whole genome/exome sequencing studies on endometrial cancers (ECs) revealed that the SPOP gene is frequently mutated. However, how SPOP mutations contribute to EC remains poorly understood. In this study, transcription factor ZBTB3 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP specifically recognizes two Ser/Thr (S/T)-rich degrons located in ZBTB3 and triggers the degradation of ZBTB3 via the ubiquitin-proteasome pathway. By contrast, EC-associated SPOP mutants are defective in regulating ZBTB3 stability. SPOP inactivation promotes endometrial cell proliferation, migration, and invasion partly through ZBTB3 accumulation. Sonic hedgehog (SHH) was found to be a transcriptional target of ZBTB3. SPOP inactivation leads to ZBTB3-dependent SHH upregulation in EC cells. RUSKI-43, a small molecule inhibitor of SHH, suppresses cell proliferation, migration, and invasion in SPOP-depleted or EC-associated SPOP mutant-overexpressed EC cells. Our data indicate that pharmacological inhibition of SHH represents a possible treatment strategy for SPOP-mutated ECs.
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PMID:SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer. 3191 63

Human cytomegalovirus (HCMV) is a ubiquitous member of the Betaherpesvirinae subfamily, causing life-threatening diseases in individuals with impaired, immature, or senescent immunity. Accordingly, HIV-infected AIDS patients, transplant recipients, and congenitally infected neonates frequently suffer from symptomatic episodes of HCMV replication. Like all viruses, HCMV has a split relationship with the host proteome. Efficient virus replication can only be achieved if proteins involved in intrinsic, innate, and adaptive immune responses are sufficiently antagonized. Simultaneously, the abundance and function of proteins involved in the synthesis of chemical building blocks required for virus production, such as nucleotides, amino acids, and fatty acids, must be preserved or even enriched. The ubiquitin (Ub) proteasome system (UPS) constitutes one of the most relevant protein decay systems of eukaryotic cells. In addition to the regulation of the turn-over and abundance of thousands of proteins, the UPS also generates the majority of peptides presented by major histocompatibility complex (MHC) molecules to allow surveillance by T lymphocytes. Cytomegaloviruses exploit the UPS to regulate the abundance of viral proteins and to manipulate the host proteome in favour of viral replication and immune evasion. After summarizing the current knowledge of CMV-mediated misuse of the UPS, we discuss the evolution of viral proteins utilizing the UPS for the degradation of defined target proteins. We propose two alternative routes of adapter protein development and their mechanistic consequences.
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PMID:Ub to no good: How cytomegaloviruses exploit the ubiquitin proteasome system. 3219 76


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