Gene expression data from FLCN-restored UOK257-2 renal cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE23614 | GEO | 2010/10/11
SECONDARY ACCESSION(S): PRJNA129945
REPOSITORIES: GEO
Similar Datasets
Project description:UOK257 cell line was derived from a BHD patient. It harbors a germline mutation in FLCN (c.1285dupC) and LOH. UOK257-2 cells were generated from UOK257 cells by introducing wildtype FLCN using retrovirus. FLCN inactivation induces TFE3 transcriptional activity by increasing its nuclear localization. Thus expression microarray was used to identify the genes regulated by FLCN and TFE3. UOK257-2 cells expressing wildtype FLCN were transfected with 1) scrambled, 2) FLCN, 3) TFE3 and 4)FLCN/TFE3 siRNAs with Lipofectamine 2000 transfection reagent. Cells were harvested 3 days after transfection and RNAs were isolated using Trizol reagent and RNeasy Mini Kit. The genes induced by FLCN siRNA and reduced by TFE3 siRNA were chosen as a candidate genes regulated by FLCN and TFE3.
2010-10-11 | E-GEOD-23614 | biostudies-arrayexpress
Project description:Targeted disruption of Flcn in mouse kidney proximal tubule gives insights into human BHD renal tumorigenesis
2014-07-28 | GSE49397 | GEO
Project description:Targeted disruption of Flcn in mouse kidney proximal tubule gives insights into human BHD renal tumorigenesis Mouse Tumor kidney tissue vs. normal kidney tissue
2014-07-28 | E-GEOD-49397 | biostudies-arrayexpress
Project description:Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene that has been linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown Here we show that FLCN loss activates E-box target genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD, yet without modifying mTORC1 activity. Surprisingly, inactivation of FLCN or its binding partners FNIP1/FNIP2 activates interferon response genes but independently of interferon. Mechanistically, FLCN loss promotes recruitment of STAT2 to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint novel prognostic biomarkers.
2021-02-11 | PXD021346 | Pride
Project description:Birt-Hogg-Dubè (BHD) syndrome is an inherited condition caused by loss-of-function mutations in the gene encoding the tumor-suppressor protein folliculin (FLCN) and frequently associated with kidney cysts and cancer. FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We previously showed that deletion of TFEB rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/TFEB/TFE3 double and triple KO mice we now show that both TFEB and TFE3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Importantly, silencing of either TFEB or TFE3 rescued tumorigenesis in patient-derived xenografts (PDXs) generated from a kidney tumor of a BHD patient. Furthermore, transcriptome analyses performed in transgenic mice, PDXs and patient tumor samples revealed TFEB/TFE3 downstream targets that may contribute to their tumorigenic activity. Our findings demonstrate in disease-relevant models that TFEB and TFE3 are key drivers of kidney tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.
2023-04-04 | PXD035450 | Pride
Project description:Renal tumors that arise in individuals with BHD Syndrome represent a molecularly distinct form of renal cancer. In addition, BHD syndrome is due to a mutation the folliculin gene (FLCN). While the folliculin gene is an important tumor suppressor gene, the molecular function of this gene is not well defined. By analyzing tumor samples that contain FLCN mutations, we demonstrate that the FLCN gene is an important regulator of mitochondrial function. Gene expression profiling of BHDS tumors and normal kidney tissues
2010-12-21 | E-GEOD-21816 | biostudies-arrayexpress
Project description:Renal tumors that arise in individuals with BHD Syndrome represent a molecularly distinct form of renal cancer. In addition, BHD syndrome is due to a mutation the folliculin gene (FLCN). While the folliculin gene is an important tumor suppressor gene, the molecular function of this gene is not well defined. By analyzing tumor samples that contain FLCN mutations, we demonstrate that the FLCN gene is an important regulator of mitochondrial function.
2010-12-21 | GSE21816 | GEO
Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive complete phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15744 phosphorylated peptides were identified, residing on 4329 phosphorylated proteins. Kinase activity inference analysis revealed that FLCN loss elevates phosphorylation of numerous kinases, including tyrosine kinases EPHA2 and MET, as well as activation of downstream MAPK1/3/6 and 8. Three non-canonical phosphorylation sites on EGFR (Tyr1125, Tyr1138 and Tyr1172) were higher phosphorylated upon FLCN loss together with enhanced phosphorylated EGFR substrates ABI, EPS8, ERRFL1, STAT1, PTK2 and CTNND1. In concordance, phosphosite specific signature analyses revealed an enrichment for EGFR signaling in FLCNNEG cells. Interestingly, we detected FLCN dependent phosphorylation of PIK3CD but no canonical downstream Akt/mTOR activation. In agreement with the induction of the E-box transcriptional gene expression signature upon FLCN loss, here we identified that phosphorylation of TFEB on Ser109, Ser114 and Ser122 is dependent on FLCN and absence of this phosphorylation results in constitutive nuclear localization of this transcription factor in FLCNNEG cells. Together, our study reveals enhanced phosphorylation of specific kinases and substrates in FLCNNEG renal epithelial cells, providing important insights in BHD-associated renal tumorigenesis and offering novel handles for the design of targeted therapies.
2022-07-11 | PXD025798 | Pride
Project description:Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The FLCN tumor suppressor complex (FLCN, FNIP1, FNIP2) has been implicated in the regulation of energy homeostasis via two metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here we reveal that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers including poor prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared to the luminal, less aggressive subtypes. We show that FLCN loss in luminal subtypes promotes tumor growth through TFE3 activation and subsequent induction of several pathways including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN deficient cells was dictated by the activation of PGC-1⍺/HIF-1⍺ pathway, which we show to be TFE3-dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Thus, FLCN loss induces TFE3-dependent breast tumor growth through activation of multiple mechanisms, including previously unreported roles in aerobic glycolysis and angiogenesis. These findings could point to a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
2020-12-23 | GSE163791 | GEO
Project description:Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disorder that is characterized by the clinical triad of benign skin tumors - so-called fibrofolliculomas, recurrent pneumothoraces due to pulmonary cysts and the formation of kidney tumors. The molecular function of Folliculin (FLCN), the protein product of the BHD gene mutated in this syndrome, has remained elusive to a large extent. Animal models such as mouse, rat and canine models have been used to elucidate parts of the pathway in which FLCN plays a role showing it to interfere with AMP-kinase and mTOR signaling. Caenorhabditis elegans provides - due to its simple genetic amenability and large brood size - the perfect tool to study signal transduction pathways in detail. Thus, we decided to examine F22D3.2 (flcn-1) - a putative orthologue of FLCN in the nematode. We established the first gene expression profiles of a strain harboring a mutation in flcn-1 compared to WTN2 allowing for a first insight into the function of this gene in C. elegans. This study examines the transcriptome of the flcn-1 mutant strain RB1035 in comparison to WTN2 in order to identify differentially regulated genes. RNA was prepared from pre-reproductive adults in both WTN2 and RB1035 (harboring a flcn-1 mutant allele, mutant worms had been backcrossed wo WTN2 8 times) using biological triplicates. RNA was labeled and hybridized to Agilent C. elegans whole genome microarrays and scanned using a Agilent Technologies Scanner G2505C US22502540.
2012-12-31 | E-GEOD-43207 | biostudies-arrayexpress