Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA314868 | ENA |
REPOSITORIES: ENA
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Project description:The exposure of skin to ultraviolet (UV) radiation results in sunburn cell (SBC) and cyclobutane pyrimidine dimer (CPD) formation and local immune suppression. However, the pathways that regulate these events are poorly understood. Here, we exposed mice to UVB to study the early cytotoxic effects in absence of E3 ubiquitin protein ligase Cbl-b. We observed that Cbl-b-/- mice developed significantly less SBCs and CPDs compared to WT mice. In addition, microarray analysis revealed that loss of Cbl-b-induced cell tolerance genes rather than DNA repair genes. Taken together, our results suggest a novel role of Cbl-b in regulating UV cytotoxicity.
2018-08-15 | GSE79073 | GEO
Project description:An antisense oligonucleotide (ASO) against E3 ubiquitin ligase IDOL in the brain significantly decreased Aβ pathology, and improved spatial learning and memory in APP/PS1 mice.
2019-12-24 | GSE142535 | GEO
Project description:Cbl (Casitas B-lineage lymphoma) is a prominent post-translational regulator of protein tyrosine kinases (PTKs) that targets activated receptors for ubiquitination-mediated degradation. However, mutations within its E3 ubiquitin ligase activity rendering RING domain are often not sufficient to induce transformation. Rather, a conserved residue (Y371) within the linker helix region (LHR) of Cbl has been a mutational hotspot in myeloproliferative diseases. Interestingly, phosphorylation of Y371 is a prerequisite for Cbl’s ability to ubiquitinate PTKs. We have previously shown that Y371 mutations affect the conformation of Cbl that can be related to its transformation potential. We wanted to investigate for any additional advantage that the Cbl-Y371 mutants could gain over their wild-type counterpart so as to explain their oncogenicity. In our current study, we wanted to investigate the transcriptome profiles of cells overexpressing WT CBL or CBL-70Z, a well-characterized oncogenic CBL mutant lacking residues 366-382 and Y371S a prevalent MDS/MPN CBL mutant. We found an interesting inverse correlationship between the transcriptome of cells expressing WT CBL and the mutant CBLs. The results from this study can be linked to the oncogenic abilities of the mutant CBLs.
2019-10-20 | GSE121176 | GEO
Project description:FBXW7 is and E3 ubiquitin ligase and is highly mutated in colorectal cancer. We used human colon organoids with engineered FBXW7 hotspot mutations to investigate novel targets of E3 ligase activity with a combined transcriptomic and proteomic approach uncovering the EGFR-MAPK pathway as highly regulated by the E3 ligase activity.
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Project description:PROteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that degrade target proteins through recruiting E3 ligases. However, their application is limited in part because few E3 ligases can be recruited by known E3 ligase ligands. In this study, we identified piperlongumine (PL), a natural product, as a covalent E3 ligase recruiter, which induces CDK9 degradation when it is conjugated with SNS032, a CDK9 inhibitor. The lead conjugate 955 can potently degrade CDK9 in a ubiquitin-proteasome-dependent manner and is much more potent than SNS-032 against various tumor cells in vitro. Mechanistically, we identified KEAP1 as the E3 ligase recruited by 955 to degrade CDK9 through a TurboID-based proteomics study, which was further confirmed by KEAP1 knockout and the nanoBRET ternary complex formation assay. In addition, PL-Ceritinib conjugate can degrade EML4-ALK fusion oncoprotein, suggesting that PL may have a broader application as a covalent E3 ligase ligand in targeted protein degradation.
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Project description:Regulation of metablism by mitochondrial MUL1 E3 ubiquitin ligase
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Project description:Regulation of the cardiac transcriptome by the E3 ubiquitin ligase Huwe1.
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Project description:Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we investigated the role of Cbl-b, an E3 ubiquitin ligase and a negative regulator of TCR signaling pathways, in establishing CD8+ T cell resistance to Treg cell-mediated suppression. First, the absence of Cbl-b rendered CD8+ T cells refractory to the suppressive effects of Treg cells in vitro. Transcriptomic analyses suggested that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-g by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. To explore our findings in vivo, we utilized tumor-bearing FoxP3DTR-eGFP mice to confirm that the adoptively transferred tumor-specific CD8+ T cells were susceptible to regulation by Treg cells in the tumor. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-g blockade. Collectively, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of IFN-g as a key mechanism which renders CD8+ T cells resistant to Treg cell-mediated suppression.
2021-12-31 | GSE189350 | GEO
Project description:M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that he E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplo-deletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.
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