UBE2J1 is the E2 Ubiquitin Conjugating Enzyme Required for Androgen Receptor Degradation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1003118 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25557700_1.fastq.gz | Fastqsanger.gz | |||
| SRR25557700_2.fastq.gz | Fastqsanger.gz | |||
| SRR25557701_1.fastq.gz | Fastqsanger.gz | |||
| SRR25557701_2.fastq.gz | Fastqsanger.gz | |||
| SRR25557702_1.fastq.gz | Fastqsanger.gz |
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Project description:The Androgen Receptor (AR) is a pivotal protein in human physiology, exerting significant influence on both male and female physiology (PMID: 18434134, 25905231). Functioning as a nuclear transcription factor, AR binds to testosterone, translocates to the nucleus, and subsequently regulates the expression of numerous genes, impacting vital cellular processes such as cell proliferation, differentiation, and apoptosis (PMID: 4810760, 25237629). The prominent role of AR in human physiology is particularly notable in the context of prostate cancer initiation, where aberrant AR signaling has been identified as a key driver in tumorigenesis (PMID: 4810760, 27057074, 37429011). However, despite the considerable success of the current anti-androgen therapeutic approach, it faces the formidable challenge of drug resistance, significantly limiting the clinical outcome for patients and necessitating the urgent development of new therapeutic approaches to overcome resistance (PMID: 26563462, 24881730, 31363002, 35582713). Notably, one key feature of antiandrogen resistance is the sustained or enhanced AR signaling observed in many resistant tumors (PMID: 26563462, 34449248, 23580326), although the underlying molecular mechanisms remain largely unclear. Protein degradation, with ubiquitination at its core, plays a critical role in cell functionality, ensuring the elimination of redundant and harmful proteins (PMID: 16738015, 33634825). This intricate process involves the attachment of small proteins called ubiquitin to target proteins, marking them for degradation. Dysregulation of ubiquitination can lead to the accumulation of oncogenic proteins, contributing to tumorigenesis and therapy resistance in various cancers (PMID: 32296023, 33004065). The degradation of proteins is a complex process that involves the coordination of E1, E2 and E3 enzymes, with E3 enzymes binding to the target protein (PMID: 21111229, 20930542). Logically, research has focused on finding E3s targeting AR for degradation but has overlooked the role that E2s play in the ubiquitination process. In recent years, E2s have been shown to dictate the how and where ubiquitin gets attached in the target protein, dictating the fate of the protein (PMID: 27002219, 19851334). Therefore, finding the E2 involved in the degradation of AR can prove to be essential. In this study, we conducted an in vivo library screening approach and identified UBE2J1 as the bona fide E2 ubiquitin conjugating enzyme for AR ubiquitination. Our results demonstrated that the frequent loss of UBE2J1 in prostate cancer leads to dysregulated and impaired AR ubiquitination and degradation. Consequently, this promotes the accumulation of AR proteins and confers resistance to antiandrogen treatment in UBE2J1-deficient prostate cancer cells. To address this, we developed an innovative ubiquitination-based AR degrader that effectively restores AR ubiquitination, thereby resensitizing prostate cancer cells to antiandrogen therapy. These findings not only unveil the pivotal role of UBE2J1 as the crucial E2 ubiquitin conjugating enzyme for AR degradation but also shed light on a novel mechanism through which advanced prostate cancer cells upregulate AR protein levels, thereby acquiring resistance to existing antiandrogen therapy. These novel insights hold the potential to inform the development of more effective therapeutic strategies against advanced prostate cancers.
2024-02-09 | GSE240305 | GEO
Project description:We identified a novel E2 ubiquitin conjugating activity within the C-terminus domain of MUC1. To determine if E2 ubiquitin conjugating activity of MUC1 is responsible for regulating expression of oncogenic genes we isolated RNA from vector control cells, MUC1 wildtype overexpression cells, and cells that express a serine mutant lacking E2 activity.
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Project description:An E2 ubiquitin conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function
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Project description:We identified a novel E2 ubiquitin conjugating activity within the C-terminus domain of MUC1. To determine if E2 ubiquitin conjugating activity of MUC1 is responsible for regulating expression of oncogenic genes we isolated RNA from vector control cells, MUC1 wildtype overexpression cells, and cells that express a serine mutant lacking E2 activity. RNA was isolated from each of the 3 cell lines, S2013.Neo, S2013.MUC1-WT, and S2013.MUC1-Ser. Gene expression was analyzed by spotted microarray and the differences in gene expression were calculated between the cell lines
2016-08-01 | E-GEOD-60339 | biostudies-arrayexpress
Project description:Proteins can be targeted for degradation by using engineered molecular conjugates to enhance their interaction with eukaryotic ubiquitination machinery. For instance, the fusion of an E3 ubiquitin ligase to a suitable target binding domain creates a biological ‘Proteolysis-Targeting Chimera’ (bioPROTAC). Here we report an analogous approach where the target is recruited directly to an E2 ubiquitin-conjugating enzyme via an attached target binding domain. We demonstrate that E2 bioPROTACs can induce the degradation of the human proteins SHP2, KRAS and Human Antigen R (HuR). Taking advantage of both rational and unbiased combinatorial screening, we identified novel SHP2 degraders that possess unusually weak affinity. Finally, we explored the proteomic impact of E2 vs. E3 bioPROTACs to inform on their wider impact on the cellular proteome.
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Project description:Neurodegenerative disorders are status in which neuronal cell death, miscommunications between synapse, and abnormal accumulation of proteins in the brain. Alzheimer’s disease (AD) is one of the age-related disorders which is most common degenerative disorders today, and strongly involved memory consolidation and cognitive in the brain. Amyloid-β and tau proteins are trigger for AD pathogenesis, and usually use for AD candidate biomarkers in the clinical research. Especially, clinical exam, brain imaging and molecular biological methods are being used to diagnosis for AD. Genome-wide association study (GWAS) is new biomedical method, and use contribute to understanding of many human diseases included brain diseases. Here, we identified ubiquitin conjugating enzyme E2 (Ube2) gene expression in the neuron through GWAS. The subfamilies of Ube2 genetic expression and inborn errors affect ubiquitin proteasome system (UPS) leading to protein degradation in the brain. We found that only Ube2h mRNA transcription was significantly increased in the blood from AD, however we did not find change of Ube2 subfamily genes expression in the blood and brain tissue. These data may provide information of diagnosis or clinical approach, and suggest that cell-free circulating Ube2h mRNA is novel potential biomarker for AD.
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