Transcriptomic of MKD (MUC1 kidney disease) patient compares to normal derived kidney epithelial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA533239 | ENA |
REPOSITORIES: ENA
Dataset's files
primary
| Action | DRS | |||
|---|---|---|---|---|
| SRR8921510_1.fastq.gz | Fastqsanger.gz | |||
| SRR8921510_2.fastq.gz | Fastqsanger.gz | |||
| SRR8921511_1.fastq.gz | Fastqsanger.gz | |||
| SRR8921511_2.fastq.gz | Fastqsanger.gz | |||
| SRR8921512_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Publications
Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.
Dvela-Levitt Moran M Kost-Alimova Maria M Emani Maheswarareddy M Kohnert Eva E Thompson Rebecca R Sidhom Eriene-Heidi EH Rivadeneira Ana A Sahakian Nareh N Roignot Julie J Papagregoriou Gregory G Montesinos Monica S MS Clark Abbe R AR McKinney David D Gutierrez Juan J Roth Mark M Ronco Lucienne L Elonga Esther E Carter Todd A TA Gnirke Andreas A Melanson Michelle M Hartland Kate K Wieder Nicolas N Hsu Jane C-H JC Deltas Constantinos C Hughey Rebecca R Bleyer Anthony J AJ Kmoch Stanislav S Živná Martina M Barešova Veronika V Kota Savithri S Schlondorff Johannes J Heiman Myriam M Alper Seth L SL Wagner Florence F Weins Astrid A Golub Todd R TR Lander Eric S ES Greka Anna A
Cell 20190701 3
Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1- ...[more]
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2019-04-18 | GSE129943 | GEO
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Project description:BACKGROUND:Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. METHODS:We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. RESULTS:After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. CONCLUSIONS:We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.
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Project description:Epithelial-mesenchymal transition (EMT) is a molecular and cellular program in which epithelial cells lose their well-differentiated phenotype and adopt mesenchymal characteristics. This process, which occurs naturally during embryogenesis, has also been shown to be associated with cancer progression and with tumor recurrence following conventional therapies. Brachyury is a transcription factor that mediates EMT during development, and is aberrantly expressed in various human cancers where it promotes tumor cell EMT, metastatic dissemination, and resistance to conventional therapies. We have recently shown that very high expression of brachyury can protect tumor cells against immune cell-mediated cytotoxicity. In seeking to elucidate mechanisms of immunotherapy resistance, we have discovered a novel positive association between brachyury and mucin-1 (MUC1). MUC1 is overexpressed in the majority of carcinomas, and it has been shown to mediate oncogenic signaling and confer resistance to genotoxic agents. We found that MUC1 is concomitantly upregulated in tumor cell lines that highly express brachyury due to an enhancement of MUC1 mRNA stability. Analysis of patient lung tumor tissues also identified a positive association between these two proteins in the majority of samples. Inhibition of MUC1 by siRNA-based gene silencing markedly enhanced the susceptibility of brachyury-expressing cancer cells to killing by tumor necrosis-related apoptosis-inducing ligand (TRAIL) and to perforin/granzyme-dependent lysis by immune cytotoxic cells. These studies confirm a protective role for MUC1 in brachyury-expressing cancer cells, and suggest that inhibition of MUC1 can restore the susceptibility of mesenchymal-like cancer cells to immune attack.
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Project description:GATA6 acts as an oncogene or tumour suppressor in different cancers. Previously, we found that aberrant expression of GATA6 promoted metastasis in cholangiocarcinoma (CCA). However, the mechanism by which GATA6 promotes metastasis in CCA is unclear. In the present study, we aimed to investigate the role of GATA6 in CCA cell epithelial-mesenchymal transition (EMT). Our results showed that GATA6 expression was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. GATA6 promoted EMT and metastasis in CCA cells in vitro and in vivo based on knockdown and overexpression analyses. ChIP-sequencing data revealed that MUC1 is a novel downstream target of GATA6. GATA6 upregulated MUC1 expression through binding to both the 1584 and 1456 GATA-motifs in the promoter region and enhancing its transcription by luciferase reporter assays and point-mutant assays. MUC1 expression was positively associated with N-cadherin and vimentin expression but negatively associated with E-cadherin expression in 91 CCA samples. In addition, MUC1 promoted EMT in CCA cells based on knockdown and overexpression analyses. Moreover, MUC1 knockdown significantly abrogated the GATA6-induced EMT in CCA cells, indicating that MUC1 promoted EMT through upregulating MUC1 in CCA cells. ?-Catenin is a putative transcriptional coactivator that regulates EMT in cancers. Our data showed that MUC1 expression was positively associated with nuclear ?-catenin expression in 91 CCA samples. MUC1 upregulated nuclear ?-catenin expression in CCA cells. Moreover, MUC1 bound to ?-catenin in CCA cells based on protein immunoprecipitation analyses. MUC1 knockdown significantly decreased the binding of MUC1 to ?-catenin, and thereby decreased nuclear ?-catenin protein levels in CCA cells, indicating that MUC1 bound to ?-catenin and increased its nuclear expression in CCA cells. Together, our results show that GATA6 promotes EMT through MUC1/?-catenin pathway in CCA, indicating potential implications for anti-metastatic therapy.
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