HOIL-1/RBCK1 promotes p53 degradation in Renal cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA490504 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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.
2024-01-26 | GSE243936 | GEO
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:Epithelial ovarian cancer (OC) is a highly heterogeneous and malignant female cancer with an overall low survival rate. p53 mutation is a predominant genetic factor thought to be responsible for poor clinical outcome. Despite the fact that ovarian clear cell carcinoma (OCCC) shows more severe prognosis, drug resistance, metastasis and recurrence compared to other OC subtypes, mutations in p53 are much less frequent. The underlying mechanisms crucial for tumorigenesis and malignancy of OC harboring wild-type (WT) p53 remain poorly understood. We found that upregulation of MEX3A, which is a dual-function protein containing a RING finger domain and an RNA binding domain, was correlated with poor survival in OC. MEX3A overexpression enhanced tumorigenic activity in RMG-1 and OVISE OCCC cell lines. In contrast, depletion of MEX3A in PA-1 ovarian teratocarcinoma cells and TOV21G OCCC cells reduced cell survival and proliferative ability in cell-based assays, as well as inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase the protein stability of WT p53. MEX3A-mediated p53 protein degradation was crucial to prevent ferroptosis and enhance tumorigenesis as p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in OC cells harboring WT p53.
2022-10-25 | GSE200509 | GEO
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
2023-01-25 | GSE223219 | GEO
Project description:Prostate cancer is the most common male cancer and androgen receptor (AR) is the major driver of the disease. Here we show that Enoyl-CoA delta isomerase 2 (ECI2) is a novel AR-target that promotes prostate cancer cell survival. Increased ECI2 expression predicts mortality in prostate cancer patients (p=0.0086). ECI2 encodes for an enzyme involved in lipid metabolism, and we use multiple metabolite profiling platforms and RNA-seq to show that inhibition of ECI2 expression leads to decreased glucose utilization, accumulation of fatty acids and down-regulation of cell cycle related genes. In normal cells, decrease in fatty acid degradation is compensated by increased consumption of glucose, and here we demonstrate that prostate cancer cells are not able to respond to decreased fatty acid degradation. Instead, prostate cancer cells activate incomplete autophagy, which is followed by activation of the cell death response. Finally, we identified a clinically approved compound, perhexiline, which inhibits fatty acid degradation, and replicates the major findings for ECI2 knockdown. This work shows that prostate cancer cells require lipid degradation for survival and identifies a small molecule inhibitor with therapeutic potential.
2017-03-03 | GSE75035 | GEO
Project description: Not available
| S-EPMC6420644 | biostudies-literature
Project description:Nrf2 activation promotes lung cancer metastasis by blocking degradation of Bach1
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Project description:The tumor suppressor P53 plays critical roles in prohibiting cancer. P53 is rarely mutated and still functional in luminal types of breast cancer. According to current knowledge, wild type P53 function is tightly controlled by post-translational modification, such as ubiquitination. Several ubiquitin ligases were shown to regulate P53 ubiquitination and protein stability. Here, we report RNF187, a RING family ubiquitin ligase, facilitates breast cancer growth and inhibits apoptosis via modulating P53 signaling. RNF187 is elevated in breast cancer and correlates with breast cancer survival only in P53 wild type groups. The bio-informatics analysis shows that RNF187 negatively correlates P53 target gene expression, such as IGFBP3 and FAS in breast cancer. RNF187 depletion inhibits breast cancer growth and facilitates cell death. RNA sequencing analysis indicates that RNF187 could be an important modifier for P53 signaling. Further experiments show that RNF187 interacts with P53 and promotes P53 degradation via facilitating P53 poly-ubiquitination in breast cancer cells. Interesting, the in vitro ubiquitin assay shows that RNF187 could directly ubiquitinate P53, which is independent of MDM2. These finding reveals a novel direct P53 regulator and a potential therapeutic target for breast cancer.
2021-09-01 | GSE183008 | GEO