HOIL-1/RBCK1 promotes p53 degradation in Renal cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119864 | GEO | 2019/03/28
REPOSITORIES: GEO
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Project description:HOIL-1/RBCK1 promotes p53 degradation in Renal cancer cells
| PRJNA490504 | ENA
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.
| S-EPMC6420644 | biostudies-literature
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: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:The proteome of clinical tissue samples diagnosed with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were evaluated analyzed along with the dataset identifier PXD022018 to establish a potential discriminative biomarker panel of proteins for these tumors subtypes.
2021-12-15 | PXD023296 | Pride
Project description:We performed CBX7 knockdown in renal cancer cells along with RNA sequencing. The expression profiling showed TNF signaling as a potential CBX7 target and the conditions were also verified in clinical samples.
2022-10-11 | GSE185630 | 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:Characterization of gene expression for each renal cell type is essential for identifying mechanisms underlying kidney physiology and pathophysiology. Here, we built a transcriptome landscape mouse renal epithelial cells by deep sequencing of all 14 mouse renal segments, upon which we developed an enrichment protocol to characterize distal nephron cells by single-cell RNA-seq. Our renal tubule expression atlas provided landscapes of gene expression and alternative splicing along the renal tubule segments. We identified, and integrated segment-specific genes with human gene nomenclature to understand the gene function and conservation. We further developed an enrichment strategy for single-cell analysis of distal nephron cells. The analysis revealed heterogeneous gene expression in DCT1-DCT2-CNT. Moreover, we identified two mosaic cell types in thick ascending limb and verified their presence in mouse kidney tissue. Our data provides a rich resource for kidney research and we provide our data user-friendly at https://esbl.nhlbi.nih.gov/MRECA/Nephron/ and https://esbl.nhlbi.nih.gov/MRECA/DCT/.
2020-11-18 | GSE150338 | 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:Mammalian kidney has very limited ability to repair or regenerate after acute kidney injury (AKI). The maladaptive repair of AKI promotes the progression to chronic kidney disease (CKD). Therefore, it is extremely urgent to explore new strategies to promote the repair/regeneration of injured renal tubules after AKI. It has been shown that hypoxia induces heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxia condition and found that MK-8617 significantly ameliorates ischemia reperfusion injury (IRI) induced acute kidney injury. We then showed that MK-8617 dramatically facilitates renal regeneration via promoting the proliferation of injured renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis- related genes were significantly upregulated with MK-8617 pretreatment. Furthermore, we showed that MK-8617 may alleviate proximal tubule injury via stabilizing HIF-1α protein specifically in renal proximal tubular cells. We also demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells, and the regeneration of renal proximal tubules. In summary, we discovered that inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI via promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.
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