Genome-wide expression change by SHARPIN knockdown in MCF-7 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77261 | GEO | 2017/01/01
SECONDARY ACCESSION(S): PRJNA309884
REPOSITORIES: GEO
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Project description:The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss of Sharpin leads to severe dermatitis due to excessive cell death in keratinocytes. Here we report two patients with SHARPIN deficiency manifesting autoinflammatory symptoms but unexpectedly, no dermatologic manifestations. Patient fibroblasts and B cells showed attenuated canonical NF-κB response and propensity to cell death mediated by TNF superfamily members. Both SHARPIN- and HOIP-deficient patients showed substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
2024-03-07 | GSE261031 | GEO
Project description:Colorectal cancer (CRC) is one of the most common cancers and a major cause of cancer mortality worldwide. Further improvements are needed for the treatment of CRC. The E3 ubiquitin ligase is an enzyme that plays an important role in regulating protein expression levels via posttranslational ubiquitin-mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In this study, using comprehensive expression analysis involving spatial transcriptomic analysis with single-cell RNA sequencing in clinical CRC datasets, we identified the ubiquitin-associated protein Shank-associated RH domain interactor (SHARPIN) as a putative driver gene located on amplified chromosome 8q. SHARPIN was overexpressed in tumor cells, and high expression of SHARPIN in tumor tissues was positively correlated with lymphatic invasion and was independently predictive of a poor prognosis in CRC patients. In vitro and in vivo analyses using SHARPIN-overexpressing or -knockout CRC cells revealed that SHARPIN upregulated MDM2, resulting in subsequent downregulation of p53, which inhibits tumor cell apoptosis and promotes tumor growth in CRC. Furthermore, SHARPIN overexpression and significant effects on survival were observed in various cancers. In conclusion, SHARPIN is a novel driver gene that potentially promotes tumor growth following apoptosis inhibition in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.
2024-02-14 | GSE255286 | GEO
Project description:Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here, we report novel mechanisms of HCC progression through Sharpin overexpression. Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in stably Sharpin-expressing cells. Versican expression increased in the majority of HCC tissues and knocking down of versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of versican transcription synergistically with Wnt/-catenin pathway activation. Furthermore, Sharpin overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes versican expression synergistically with the Wnt/-catenin pathway, potentially contributing to HCC development. A Sharpin/versican axis could be an attractive therapeutic target for this currently untreatable cancer.
2017-01-23 | GSE87149 | GEO
Project description:Sharpin, a multifunctional adaptor protein with oncogenic properties, regulates several signalling pathways. For example, Sharpin enhances signal-induced NF-κB signalling as part of the linear ubiquitin assembly complex (LUBAC) and inhibits integrins, the T cell receptor, caspase1 and PTEN. However, despite recent insights into Sharpin and LUBAC function, a systematic approach to identify signalling pathways regulated by Sharpin has not been reported. Here, we present the first ‘Sharpin interactome’, which identifies a large amount of novel potential Sharpin interactors. These data suggest that Sharpin and LUBAC might regulate a larger number of biological processes than previously identified, such as endosomal trafficking, RNA processing, metabolism and cytoskeleton regulation. Importantly, using the Sharpin interactome we have identified a novel role for Sharpin in lamellipodium formation. We demonstrate that Sharpin interacts with the Arp2/3 complex, a protein complex that catalyses actin filament branching, and that Sharpin and Arp2/3 colocalize in lamellipodia. We identified the Arp2/3-binding site in Sharpin and demonstrate using a specific Arp2/3-binding deficient mutant that the Sharpin-Arp2/3 interaction promotes lamellipodia formation in a LUBAC-independent fashion.
2017-08-11 | PXD004734 | Pride
Project description:One of the ubiquitin ligases, LUBAC, is a trimetric complex composed of SHARPIN, HOIL-1, and HOIP. LUBAC works at the proximal TCR signaling pathway allowing normal Treg development. We used microarrays to detail the global programme of gene expression underlying LUBAC-mediated signaling pathway in Treg cells.
2019-08-08 | GSE108793 | GEO
Project description:Mice lacking components of the linear ubiquitin chain assembly complex (LUBAC) exhibit defects in thymocyte differentiation. To determine how two LUBAC components, HOIL and SHARPIN, mediate their effects, we purified thymocytes from CD4Cre Hoil-fl/fl or Sharpin-cpdm mice and compared their transcriptional profile to WT controls. We focused on the CD69+ MHCI low and CD69+ MHCI high subsets that follow positive selection.
2016-10-30 | GSE74552 | GEO
Project description:The cytosolic protein Sharpin is as a component of the linear ubiquitin chain assembly complex (LUBAC), which regulates NF-κB signaling in response to specific ligands. Its inactivating mutation in Cpdm (chronic proliferative dermatitis mutation) mice causes multi-organ inflammation, yet this phenotype is not transferable into wildtype mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, but the cellular and molecular causes of this phenotype remained to be established. Here we have applied non-decalcified histology together with cellular and dynamic histomorphometry to perform a thorough skeletal phenotyping of Cpdm mice. We show that Cpdm mice display trabecular and cortical osteopenia, solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. We additionally found that Cpdm mice display a severe disturbance of articular cartilage integrity in the absence of joint inflammation, supporting the concept that Sharpin-deficiency affects mesenchymal cell differentiation. Consistently, Cpdm mesenchymal cells displayed reduced osteogenic capacitiy ex vivo, yet this defect was not associated with impaired NF-κB signaling. A molecular comparison of wildtype and Cpdm bone marrow cell populations further revealed that Cpdm mesenchymal cells produce higher levels of Cxcl5 and lower levels of IL1ra. Collectively, our data demonstrate that skeletal defects of Cpdm mice are not caused by chronic inflammation, but that Sharpin is as a critical regulator of mesenchymal cell differentiation and gene expression. They additionally provide an alternative molecular explanation for the inflammatory phenotype of Cpdm mice and the absence of disease transfer by hematopoetic stem cell transplantation. Unsorted bone marrow cells from wildtype and Cpdm mice were cultured for 10 days in the presence of ascorbic acid and ß-glycerophosphate to induce osteogenic differentiation
2015-09-07 | E-GEOD-61299 | biostudies-arrayexpress
Project description:The cytosolic protein Sharpin is as a component of the linear ubiquitin chain assembly complex (LUBAC), which regulates NF-κB signaling in response to specific ligands. Its inactivating mutation in Cpdm (chronic proliferative dermatitis mutation) mice causes multi-organ inflammation, yet this phenotype is not transferable into wildtype mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, but the cellular and molecular causes of this phenotype remained to be established. Here we have applied non-decalcified histology together with cellular and dynamic histomorphometry to perform a thorough skeletal phenotyping of Cpdm mice. We show that Cpdm mice display trabecular and cortical osteopenia, solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. We additionally found that Cpdm mice display a severe disturbance of articular cartilage integrity in the absence of joint inflammation, supporting the concept that Sharpin-deficiency affects mesenchymal cell differentiation. Consistently, Cpdm mesenchymal cells displayed reduced osteogenic capacitiy ex vivo, yet this defect was not associated with impaired NF-κB signaling. A molecular comparison of wildtype and Cpdm bone marrow cell populations further revealed that Cpdm mesenchymal cells produce higher levels of Cxcl5 and lower levels of IL1ra. Collectively, our data demonstrate that skeletal defects of Cpdm mice are not caused by chronic inflammation, but that Sharpin is as a critical regulator of mesenchymal cell differentiation and gene expression. They additionally provide an alternative molecular explanation for the inflammatory phenotype of Cpdm mice and the absence of disease transfer by hematopoetic stem cell transplantation.
2015-09-07 | GSE61299 | GEO
Project description:Skin is an essential organ that preserves the integrity of the body and the maintenance of lipid content and composition is essential for proper epidermal barrier function. SHANK-associated RH domain interacting protein-deficient mice spontaneously develop a chronic proliferative dermatitis with similarities to atopic dermatitis in humans. To learn about changes in the epidermal lipid-content in male and female mice during disease progression, we used 18 male and 18 female wild-type mice and 3 groups of littermates mice with dermatitis (6 male and 6 female each) divided according to the stage of disease: non-lesional, established and advanced. A mass-spectrometry strategy for biomarker discovery termed multiple-reaction monitoring-profiling was used to detect and monitor 1030 lipid ions present in the epidermis samples. Univariate analysis was performed to link lipids to disease stage in a sex-dependent or independent manner. An elastic-net regression model was built using the top 10 lipid features to predict disease progression. Individual samples were classified into their corresponding disease stage groups with an accuracy of 0.90 (95% CI:0.86, 0.93). Multiple-reaction monitoring-profiling paired with machine-learning identified predictive biomarkers of dermatitis in mice and may provide the basis for a molecular diagnostic approach to atopic dermatitis.
2019-06-03 | MSV000083884 | MassIVE
Project description:Skin inflammation is a complex process implicated in various dermatological disorders. The chronic proliferative dermatitis (cpd) phenotype driven by the cpd mutation (cpdm) in the Sharpin gene is characterized by dermal inflammation and epidermal abnormalities. TNF and caspase-8-driven cell death causes the pathogenesis of Sharpincpdm mice, however, the role of MIB2, a pro-survival E3 ubiquitin ligase involved in TNF-signalling, in skin inflammation remains unknown. Here we demonstrate that MIB2 antagonises inflammatory dermatitis in the context of the cpd mutation. Surprisingly, the role of MIB2 in limiting skin inflammation is independent of its known pro-survival function and E3 ligase activity. Instead, MIB2 enhances the production of wound healing molecules, G-CSF and Eotaxin, within the skin. This discovery advances our comprehension of inflammatory cytokines and chemokines involved in cpdm pathogenesis, and highlights the significance of MIB2 in inflammatory skin disease that is independent of its ability to regulate TNF-induced cell death.
2024-01-25 | PXD045850 | Pride