Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1032858 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26543913_1.fastq.gz | Fastqsanger.gz | |||
| SRR26543913_2.fastq.gz | Fastqsanger.gz | |||
| SRR26543914_1.fastq.gz | Fastqsanger.gz | |||
| SRR26543914_2.fastq.gz | Fastqsanger.gz | |||
| SRR26543915_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
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Project description:The yeast 20S proteasome was analyzed using native mass spectrometry combined with UVPD, HCD, and vT-ESI. Nano-LC-MS-EThcD was used to characterize the primary sequence features of the 20S subunits.
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Project description:Reduction in the cellular levels of the cyclin kinase inhibitor p27kip1 are frequently found in many human cancers and correlate directly with patient prognosis. Specifically ubiquitin dependent proteasomal turnover has been shown to cause reduced p27 expression in many human cancers. We recently demonstated that expression of a stabilized version of p27kip1 (p27kip1T187A) in a genetically modified mouse significantly reduced the number of intestinal adenomatous polyps which progressed to invasive carcinomas. Based on this work we set out to identify compounds which lead to a re-expression of p27 in cancer tissues. In this work we identify Argyrin A a compound derived from myxobacterium archangium gephyra as a potent inducer of p27kip1 expression. Argyrin A induces apoptosis in human colon cancer xenografts and tumor vasculature in vivo leading to a profound reduction in tumor size at well tolerated levels. Argyrin A functions are strictly dependent on the expression of p27kip1 as neither tumor cells nor endothelial cells which do not express p27kip1 respond to this compound. Surprisingly the molecular mechanism by which Argyrin A exerts its p27 dependent biological function is through a potent inhibition of the 20S proteasome. Experiment Overall Design: MCF7 cells were incubated with proteasome inhibitors bortezomib or Argyrin A or proteasome activity was reduced by treatment with siRNA against proteasomal subunits and gene expression profiles were determined at different timepoints thereafter.
2008-06-16 | E-GEOD-8565 | biostudies-arrayexpress
Project description:We compared the expression changes in Ewing sarcoma cell lines following treatment with 2 known 20S proteasome inhibitors versus 2 novel compounds
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Project description:Proteasome inhibitors are important chemotherapeutics in the treatment of multiple myeloma, but they are currently used empirically as no markers of sensitivity have been validated. We have identified expression of tight junction protein (TJP) 1 as being associated with sensitivity of plasma cells in vitro and in vivo to proteasome inhibitors. TJP1 suppressed expression of genes in the major histocompatibility class II region, including two catalytically active immunoproteasome subunits, thereby decreasing proteasome activity, a critical determinant of proteasome inhibitor sensitivity. This occurred through suppression by TJP1 of signaling through the epidermal growth factor receptor/Janus kinase 1/signal transducer and activator of transcription 3 pathway. In the clinic, high TJP1 expression in myeloma patients was associated with a significantly higher likelihood of responding to bortezomib, and with a longer time-to-progression after treatment. Taken together, these data support the use of TJP1 as a biomarker of sensitivity and resistance to proteasome inhibitors. To further elucidate mechanisms of bortezomib resistance, we developed human-derived multiple myeloma cell lines with a 4-fold or greater resistance to bortezomib. Then total RNA for bortezomib resistant (BR) and wild type (WT) was extracted and used for comparison by gene expression profiling.
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Project description:The 20S proteasome is responsible for the catalytic activity of all proteasome complexes. Structural constraints mean that only unfolded, extended polypeptide chains may enter the catalytic core of the 20S proteasome. Here we conducted a comprehensive analysis of the 20S CP substrates in-vitro. We revealed that the 20S CP substrates are highly structually disordered. The 20S proteasome substrate group, termed 20S-IDPome are characterized by having significantly more protein binding partners, more post-translational modification sites and are highly enriched for RNA binding proteins. Remarkably, we found that low complexity proteins with prion-like domain which interact with GR or PR di-peptide repeats are the most preferential 20S proteasome substrates. Our finding suggests roles of the 20S proteasome in gene transcription and formation of phase-separated granules.
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Project description:Proteasome dysfunction is emerging as a novel pathomechanism for the development of chronic obstructive pulmonary disease (COPD), a major leading cause of death in the world. Cigarette smoke is one of the main risk factors for COPD and has been shown to impair proteasome function in vitro and in vivo. Importantly, proteasome activity is inhibited in COPD lungs while expression levels of proteasome subunits are not altered. In the present study, we dissected the molecular changes induced by cigarette smoke on proteasome function in lung epithelial cells and mouse lungs. We analyzed the integrity, composition, and the interactome of isolated 26S proteasome complexes from smoke-exposed cells and mouse lungs. Moreover, we applied native MS analysis to investigate whether reactive compounds of cigarette smoke directly modify and inhibit the 20S proteasome complex. Our data reveal that the 20S proteasome is slightly destabilized in the absence of any dominant modification of proteasomal proteins. 26S pulldown and stoichiometry analysis indicated that 26S proteasome complexes become instable in response to cigarette smoke exposure. Of note, the interactome of the 26S was clearly altered in smoke-exposed mouse lungs possibly reflecting an altered cellular composition in the lungs of the smoke-exposed mice. Taken together, our results suggest that cigarette smoke induces minor but detectable changes in the stability and interactome of 20S and 26S proteasome complexes which might contribute in a chronic setting to imbalanced proteostasis as observed in chronic lung diseases associated with cigarette smoking.
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Project description:Exosomal miR-1290 and miR-375 as prognostic markers in castrate resistant prostate cancer
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Project description:For many years, the ubiquitin-26S proteasome degradation pathway was considered the principal route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by an ubiquitin-independent mechanism mediated by the core 20S proteasome itself. The fact that half of cellular proteasomes are free 20S complexes suggests that degradation by this complex is not limited to rare cases. Identifying 20S proteasome substrates is challenging, as different pools of the same protein can be sent to degradation via either 20S or 26S proteasomes. Hence, current knowledge regarding the repertoire of 20S proteasome substrates mainly originates from individual case studies. Here, in an effort to unravel the global repertoire of substrates degraded by the 20S proteasome, we used an advanced mass spectrometry approach coupled with biochemical and cellular analysis. Our analysis enabled the identification of hundreds of 20S proteasome substrates. In addition to proteins that are degraded to completion, we also identified proteins that undergo specific cleavage by the 20S proteasome, at their N- or C- termini, to possibly tune their function. We also found that 20S substrates are significantly enriched with RNA- and DNA-binding proteins that contain intrinsically disordered regions. The vast majority of them are localized in the nucleus and stress granules. Further, we demonstrate that oxidized proteasomes have reduced proteolytic activity compared to naïve proteasomes, which we propose is an adaptive advantage under conditions of cellular stress. Whereas oxidized protein substrates, rather than being folded proteins that lost their native structure due to the stress, actually display a higher degree of structural-disorder than naïve proteins. In summary, here we shed light on the nature of the 20S substrates, providing critical insight into the biological role of the 20S proteasome.
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Project description:An assessment of prognostic immunity markers in breast cancer
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Project description:Degradation of intrinsically disordered proteins (IDPs) by a non-26S proteasome process does not require proteasomal targeting by polyubiquitin. However, whether and how IDPs are recognized by the non-26S proteasome, including the 20S complex, remains unknown. Analyses of protein interactome datasets revealed that the 20S proteasome subunit, PSMA3, preferentially interacts with many IDPs. Employing in vivo and cell-free experiments, it was found that a 69-amino-acids-long fragment at the C-terminus of PSMA3 is sufficient to bind the disordered protein p21. A recombinant PSMA3 C-terminus 69 fragment is sufficient to interact with many IDPs, and is therefore designated an IDP trapper. A recombinant IDP trapper blocks the degradation of many IDPs in vitro by the 20S proteasome, possibly by competing with the native trapper. In addition, over a third of the PSMA3 trapper-binding proteins have previously been identified as 20S proteasome substrates, and based on published datasets many of the trapper binding proteins are associated with the intracellular proteasomes. The PSMA3-trapped IDPs that are proteasome substrates have the unique features previously recognized as characteristic 20S proteasome substrates in vitro. We propose a model whereby the PSMA3 C-terminal region traps a subset of IDPs to facilitate their proteasomal degradation.
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