Impact of E2 ubiquitin conjugating activity of MUC1 on gene expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60339 | GEO | 2016/08/01
SECONDARY ACCESSION(S): PRJNA258057
REPOSITORIES: GEO
Similar Datasets
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
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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:UBA1 is the primary E1 ubiquitin-activating enzyme, regulating stability and function of numerous proteins via initiating their ubiquitination. Decreased or insufficient ubiquitination can cause or drive aging and many deadly diseases. Therefore, a small-molecule UBA1 activity enhancer could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis is a potent UBA1 activity enhancer. Auranofin binds to the UBA1’s ubiquitin fold domain in vitro with a KD of 5.19 nM. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of five representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. This study discovered the first small-molecule UBA1 activity enhancer, providing a much-needed tool for UBA1 research and therapeutic exploration.
2023-07-10 | PXD042558 | Pride
Project description:Supporting .raw data for "Functional conservation and divergence of the helix-turn-helix motif of E2 ubiquitin-conjugating enzymes", DOI: 10.15252/embj.2021108823
Related to Figure 1E and EV1A.
2021-11-17 | MSV000088403 | MassIVE
Project description:Rad6 E2 ubiquitin-conjugating enzyme and Bre1 E3 ubiquitin ligase catalyze histone H2B Lysine-123 monoubiquitination (H2Bub1), which stabilizes nucleosomes and regulates the trans-histone H3K4 and K79 methylation during gene transcription and other nuclear processes. The interaction interfaces within the Rad6-Bre1-containing H2B ubiquitin-conjugating complex has remained unknown. By solving the crystal structure of Rad6 along with a non-RING domain N-terminal region of Bre1, we report a beta-turn in Rad6's so-called backside region away from catalytic pocket as a binding site for a homodimer of Bre1 E3 ligase. Using quantitative ChIP-seq or ChIP-Rx, we further demonstrate that Rad6's backside beta-turn residues also govern the chromatin binding dynamics of the Rad6-Bre1 complex.
2022-10-24 | GSE139633 | GEO
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.
2020-12-31 | GSE147792 | GEO
Project description:The cyclic oligonucleotide-based anti-phage signalling system (CBASS) is a typeof innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS utilizes cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homolog of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, we report that a bacterial E2 enzyme regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C-terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond, and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.
2024-02-27 | PXD050178 | iProX
Project description:Covalent modifications of proteins with ubiquitin and ubiquitin-like molecules are instrumental to most, if not all biological processes. However, identifying the E3 ligase responsible for these modifications remains a major bottleneck in ubiquitin research. Here, we have developed an E2-thioester-driven identification (E2~dID) method for the targeted identification of substrates of specific E2 and E3 enzyme pairs. E2~dID exploits the central position of E2 conjugating enzymes in the ubiquitination cascade and provides in vitro generated biotinylated E2~ubiquitin thioester conjugates as the sole source for ubiquitination in extracto. This enables purification and identification of modified proteins by mass spectrometry under stringent conditions independently of the biological source of the extract. We demonstrate the sensitivity and specificity of E2-dID by identifying and validating substrates of the APC/C in human cells. Finally, performing E2~dID with SUMO in S. cerevisiae we show that E2-dID can be easily adapted to other ubiquitin-like modifiers and experimental models.
2019-04-03 | PXD008624 | Pride
Project description:Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionzied the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function , sensitizing PI3K inhibitors, metabolism reprogramming , kinome rewiring, modulation of the proteosome, and many others. The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. By transcriptional profiling of the HR(+) breast cancer cell lines treated with the three CDK4/6 inhibitors, we have uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. These three E2 enzymes modulate a number of E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. Our study provide a novel link between CDK4/6 inhibitor and UPP which could have important implications in cancer biology.
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