Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

EGR1 overexpression in HeLa cells [EGR1oe_RNAseq]

ABSTRACT: Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE209896 | GEO | 2023/02/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

EGR1 ChIPseq in HeLa cells at 6 hours of starvation [ChIPseq_HeLa_STV]

Project description:Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.

2023-02-12 | GSE218786 | GEO

Time course of starvation in HeLa cells [STV_time course_RNAseq]

2023-02-12 | GSE218784 | GEO

siEGR1 in HeLa cells at 6 hours of starvation [siEGR1_6h_RNAseq]

2023-02-12 | GSE209897 | GEO

HeLa-FLCN KO upon Trametinib treatment [Trametinib_RNAseq]

2023-02-12 | GSE209898 | GEO

TFEB AND TFE3 DRIVE KIDNEY CYSTOGENESIS AND TUMORIGENESIS

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

The Folliculin-Fnip1 pathway deleted in human Birt-Hogg-Dube syndrome is required for B cell development.

Project description:Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disorder characterized by hamartomas of skin follicles, cystic lung disease, and renal neoplasia. Affected individuals carry heterozygous mutations in Folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney malignancies, Folliculin has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germline deletion of Flcn results in early embryonic lethality in animal models. We here describe mice deficient in the newly characterized Folliculin-Interacting Protein 1 (Fnip1). In contrast to Flcn, Fnip1-/- mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is independent of mTOR activity. We show that this developmental arrest results at least in part from impaired V(D)J recombination and caspase-induced cell death, and that pre-recombined V(D)J and Bcl2 transgenes reconstitute pre-B and mature B cell populations respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1-/- mice. Our studies thus demonstrate that the Flcn-Fnip complex deregulated in BHD syndrome is absolutely required for B cell differentiation and that it functions both through mTOR dependent and independent pathways. RNASeq data for two pro-B cell subsets (fraction B and CC') isolated from wt and Fnip1-/- mice

2012-06-16 | E-GEOD-38741 | biostudies-arrayexpress

Phosphoproteomcs of the folliculin negative cancer cell line UOK257 +/- lentiviral rescue construct

2022-07-11 | PXD030237 | Pride

The Folliculin-Fnip1 pathway deleted in human Birt-Hogg-Dube syndrome is required for B cell development.

2012-06-16 | GSE38741 | GEO

Phosphoproteomic analysis of the Folliculin (FLCN) tumor suppressor reveals FLCN-dependent kinase signaling and TFEB regulation

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

Loss of FLCN-FNIP1/2 Induces a Non-Canonical Interferon 1 Response in Human Renal Tubular Epithelial Cells

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data