HOIL-1/RBCK1 promotes p53 degradation in Renal cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA490504 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7822421_1.fastq.gz | Fastqsanger.gz | |||
| SRR7822421_2.fastq.gz | Fastqsanger.gz | |||
| SRR7822422_1.fastq.gz | Fastqsanger.gz | |||
| SRR7822422_2.fastq.gz | Fastqsanger.gz | |||
| SRR7822423_1.fastq.gz | Fastqsanger.gz |
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Project description:We performed RBCK1 depletion in renal cancer cells along with RNA sequencing. The expression profiling showed p53 signaling as a potential RBCK1 target and the conclusions were also verified in clinical samples.
2019-03-28 | GSE119864 | GEO
Project description:Despite the promise of targeted tyrosine kinase inhibitors (TKIs), such as sunitinib, in the extension of survival time in patients with clear cell renal cell carcinoma (ccRCC) progression or metastasis, the patients eventually succumb to inevitable drug resistance. Protein degradation executed by the ubiquitin-dependent proteasome system played an important role in determining the sensitivity of ccRCC to sunitinib. Here, we applied the bioinformatic analysis to identify that E3 ligase RBCK1 was elevated in the sunitinib-resistant renal cancer cell lines or patient specimens. The subsequent in vitro or in vivo studies demonstrated that RBCK1 contributed to decreasing the sensitivity of ccRCC to sunitinib. Then, we showed that inhibition of RBCK1 activated the AKT and MAPK signaling pathways, which might be one of the main reasons why RBCK1 induces sunitinib resistance in ccRCC cells. Mechanistically, our results indicated that RBCK1 promotes the degradation of ANKRD35 and that ANKRD35 destabilizes MITD1 by binding with SUMO2 in ccRCC cells. In addition, we showed that the RBCK1-ANKRD35-MITD1-ANXA1 axis regulates the phosphorylation of AKT and ERK and contributes to the dysregulation of sunitinib in ccRCC cells. Therefore, we identified a novel mechanism for regulating the sensitivity of sunitinib in ccRCC. Therefore, we elucidated a novel mechanism by which RBCK1 regulates sunitinib sensitivity in ccRCC.
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Project description:Liver cancer claims over 800,000 human deaths each year. Liver cancer is notoriously refractory to conventional therapeutics. Further insight into the etiology carries promise for innovative diagnostics and therapeutics. Tumor progression is governed by interplay between tumor promoting genes and suppressor genes. BRD4, an acetyl-lysine binding protein, plays a critical role in development and human diseases. In many cancer types, BRD4 is overexpressed and promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains elusive. As BRD4 has risen as a promising therapeutic target, to understand the mechanism regulating BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we find BRD4 protein level in liver cancer is significantly regulated by P53, the most frequently dysregulated tumor suppressor. We identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. We then show P53 promotes BRD4 protein degradation. Mechanistically, P53 represses the transcription of USP1, a deubiquitinase, through P21-RB. We show USP1 is a deubiquitinase of BRD4, which increases its stability. We show the pro-tumor role of USP1 is partially mediated by BRD4 and the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB-USP1-BRD4 axis in liver cancer.
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Project description:Loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1) results in disruption of the linear ubiquitination assembly complex (LUBAC). Impairment of LUBAC results in impaired NF-kB activation in response to TNF and IL-1b in fibroblastic cells, but also display enhanced pro-inflammatory responses to TNF and IL-1b in leukocytes. Autosomal recessive complete human HOIL-1/RBCK1 deficiency is a new disorder with unbalanced cellular responses to pro-inflammatory cytokines, resulting in the paradoxical association of auto-inflammation and pyogenic bacterial disease, as well as the surprising development of muscular amylopectinosis. The genome-wide gene expression analysis showed that human HOIL-1 deficiency results in impaired NF-B activation in response to TNF- and IL-1 in fibroblastic cells.
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Project description:P53-P21-RB pathway promotes BRD4 degradation in liver cancer through decreasing USP1 transcription
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Project description:In the healing process of myocardial infarction, cardiac fibroblasts are activated to produce collagen, leading to adverse remodeling and heart failure. Our previous study showed that ASPP1 promotes cardiomyocyte apoptosis by enhancing nuclear trafficking of p53. We thus explored the influence of ASPP1 on myocardial fibrosis and the underlying mechanisms. Here, we observed ASPP1 was increased after 4 weeks of MI. Both global and myofibroblast knockout of ASPP1 in mice mitigated cardiac dysfunction and fibrosis after MI. Strikingly, ASPP1 produced opposite influence on p53 level and cell fate in cardiac fibroblasts and cardiomyocytes. Knockdown of ASPP1 increased p53 level and inhibited the activity of cardiac fibroblasts. ASPP1 accumulated in the cytoplasm of fibroblasts while the level of p53 was reduced following TGF-1 stimulation; however, inhibition of ASPP1 increased p53 level and promoted p53 nuclear translocation. Mechanistically, ASPP1 directly bound to deubiquitinase OTUB1, thereby promoting the ubiquitination and degradation of p53, attenuating myofibroblast activity and cardiac fibrosis, and improving heart function after MI.
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Project description:Exposure to hypoxia requires adaptive mechanisms for survival. During acute hypoxia, Na,K-ATPase endocytosis in alveolar epithelial cells (AEC) occurs via protein kinase C zeta (PKCζ) phosphorylation of α1- Na,K-ATPase independently of the hypoxia inducible factor (HIF). However, exaggerated Na,K-ATPase down-regulation leads to cell death. Here we report that during prolonged hypoxia plasma membrane Na,K-ATPase levels were maintained at ~50% of normoxic values due to HIF mediated regulation of HOIL-1L which targets PKCζ for degradation. Silencing HOIL-1L in the lung epithelium prevented PKCζ degradation causing Na,K-ATPase downregulation. Accordingly, HIF regulation of HOIL-1L targets the phosphorylated PKCζ for degradation and serves as an hypoxia-adaptive mechanism to stabilize the Na,K-ATPase avoiding significant lung injury.
2018-02-14 | GSE102107 | GEO
Project description:Clear cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia PML protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation, and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.
2024-04-23 | GSE246846 | GEO
Project description:Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and the incidence of RCC continues to rise worldwide. Although RCC can be treated with surgery at an early stages, the five-year survival rates have been observed to decline dramatically in patients with advanced disease. Most patients with RCC treated with cytotoxic or targeted drugs will develop resistance at some point during therapy. Thus, it is necessary to identify novel therapeutic targets for RCC. Here, we found that RANBP2-type and C3HC4-type zinc finger-containing 1 (RBCK1) expression was upregulated in human RCC samples. Analysis of multiple public databases revealed the correlation between RBCK1 expression and poor prognosis in RCC patients. Subsequently, we performed RBCK1 depletion experiments in RCC cells that severely affected the in vivo and in vitro proliferation of renal cancer cells. The effects of RBCK1 on cell proliferation could be rescued with p53 expression knockdown in two cell lines expressing wild-type p53. Further experiments demonstrated that RBCK1 could facilitate p53 poly-ubiquitination and degradation by direct interaction with p53. Together, our results show that RBCK1 may serve as a promising target for RCC therapy by restoring p53 functions.
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Project description:Emergency myelopoiesis (EM) is critical for immune defense against pathogens, which requires rapid replenishing of mature myeloid cells. The EM process involves a rapid cell cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs). How this cell cycle switch is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB) mobilized HSPCs with ATG7 knock-down or HSPCs derived from ATG7-/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation at MP stage during myeloid/granulocytes differentiation. ATG7 deficient MPs show substantially elevated P53 protein and up-regulation of P53 signaling pathway genes. Mechanistically, ATG7 dependent autophagy mediates P53 degradation in lysosome that allows normal proliferation of MPs. Together, we reveal an essential role of autophagy for P53 degradation in cell cycle switch during human myelopoiesis
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