Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA136821 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR090229.fastq.gz | Fastqsanger.gz | |||
| SRR090230.fastq.gz | Fastqsanger.gz | |||
| SRR090231.fastq.gz | Fastqsanger.gz | |||
| SRR090232.fastq.gz | Fastqsanger.gz | |||
| SRR090233.fastq.gz | Fastqsanger.gz |
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Project description:The human tumor antigen PRAME (Preferentially expressed antigen of melanoma) is frequently overexpressed in tumors. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumorigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. Genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at NF-Y promoters that are transcriptionally active, suggesting a role in gene activation. Our results are consistent with the involvement of the PRAME ubiquitin ligase complex in NF-Y-mediated transcriptional regulation. ChIP-seq binding profiles of PRAME (ChIP-seq using the preimmune serum was used as negative control), NFYA, and NFYB, and expression analysis by RNA-seq in K562 human leukemia cell line
2011-07-29 | E-GEOD-26439 | biostudies-arrayexpress
Project description:The human tumor antigen PRAME (Preferentially expressed antigen of melanoma) is frequently overexpressed in tumors. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumorigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. Genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at NF-Y promoters that are transcriptionally active, suggesting a role in gene activation. Our results are consistent with the involvement of the PRAME ubiquitin ligase complex in NF-Y-mediated transcriptional regulation.
2011-07-29 | GSE26439 | GEO
Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation.
2015-05-01 | GSE59354 | GEO
Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation. RNAseq experiments of E13.5 murine embryonic fibroblasts (MEFs) derived from animals in which Usp28 was either deleted (-/-), wildtype (+/+) or heterozygous (+/-). In a first set of experiments immortalized MEFs of all three genotypes were analysed in biological triplicates. In a second set of experiments immortalized and Ras transformed MEFs of all three genotypes and MEFs which overexpress USP28 (+/+/+) where sequenced in duplicates.
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Project description:Preferentially Expressed Antigen of Melanoma (PRAME) is a cancer-testis antigen that is expressed in subsets of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), collectively termed keratinocyte carcinomas (KC). PRAME functions as a transcriptional co-repressor of retinoid signaling by guiding enhancer of zeste homologue 2 (EZH2), a repressive histone methyltransferase, to retinoic acid response elements (RARE) found in gene promoters. The functions and therapeutic relevance of PRAME expression in KC have not been investigated. In the present study, we evaluated the implications of PRAME expression upon KC development and response to retinoid-based therapeutics. High PRAME expression in tumors was negatively correlated with epidermal differentiation gene signatures. Similarly, PRAME overexpression (OE) downregulated epidermal differentiation gene signatures, and impaired epidermal differentiation. PRAME OE also attenuated retinoid-induced RARE activation, growth suppression and differentiation responses. Conversely, low-PRAME tumors and PRAME-depleted KC cells possessed enrichment of epidermal differentiation gene signatures. PRAME depletion also restored retinoid-induced RARE activation, suppression of KC growth, keratinization suppression in SCC cells and cell death signaling in BCC cells. Furthermore, EZH2 inhibitors potentiated the retinoid-induced RARE activation and suppress the growth of PRAME-expressing BCC and cSCC cells. We demonstrate that PRAME confers retinoid resistance in KC, and we contend that PRAME-mediated retinoid resistance in KC may be overcome by targeting EZH2.
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Project description:Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-aminoquniolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for development of cancer-specific therapeutics.
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Project description:E3 ubiquitin ligases of the Cullin RING Ligase (CRL) family assemble into multiprotein complexes to diversify substrate adaptors and ensure selectivity in substrate engagement for degradation. Here we show a novel mechanism whereby mutations in substrate adaptors can drive neo-substrate degradation in cancer. KBTBD4 is a CRL3 substrate adaptor harbouring recurrent indel mutations in a subset of non-WNT/non-SHH medulloblastomas. We show that these mutations, arising in the substrate recognition domain of KBTBD4, promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. We observe that this neomorphic activity of KBTBD4 mutants induces changes in epigenetic markers and significant alterations in transcription, diverting normal cellular programmes towards increased stemness. These results highlight mutation-driven neomorphic E3 ligase activity as a previously unrecognised mechanism in tumorigenesis, with implications for medulloblastoma pathogenesis and treatment.
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2014-10-06 | E-GEOD-48196 | biostudies-arrayexpress