Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis (Tunicamycin)

ABSTRACT: In response to a variety of upstream growth and oncogenic signals, the mechanistic target of rapamycin complex 1 (mTORC1) promotes anabolic metabolism, in part, through activation of downstream transcription factors. The transcription factor activating transcription factor 4 (ATF4) has been previously shown to function downstream of mTORC1 signaling to promote de novo purine synthesis and this activation of ATF4 can occur independently of the canonical activation of ATF4 through the integrated stress response (ISR). Here, we show that ATF4 activation through mTORC1 signaling drives a specific transcriptional program through ATF4 which is comprised of only a subset of genes involved in the broader cellular stress response. We find genes involved in amino acid uptake, biosynthesis, and charging by tRNA synthetases display transcriptional changes downstream of both mTORC1 and ATF4. We discovered that ATF4 activation contributes to the mTORC1-stimulated increase in protein synthesis, highlighting the importance of these transcriptional changes. Additionally, we observe regulation of the cystine transporter SLC7A11 by ATF4. We show that SLC7A11 is important for cell survival and is one mechanism by which cells with active mTORC1 signaling produce glutathione. Thus, ATF4 downstream of mTORC1 signaling regulates protein and glutathione synthesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE158605 | GEO | 2020/09/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation

Project description:Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, integrated proteomic and functional analyses reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis but also GPX4 protein synthesis. Mechanistically, cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the mTORC1-4E-BP signaling axis. Pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers (FINs) to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a hitherto unrecognized regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest to use the combination of mTORC1 inhibitors and FINs in cancer treatment.

2020-08-25 | MSV000086009 | MassIVE

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis (Tunicamycin)

Project description:The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis (Tunicamycin)

| PRJNA665968 | ENA

mTORC1 balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4

Project description:The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that is commonly deregulated in human diseases. Here we find that mTORC1 controls a transcriptional program encoding amino acid transporters and metabolic enzymes through a mechanism also used to regulate protein synthesis. Bioinformatic analysis of mTORC1-responsive mRNAs identified a promoter element recognized by activating transcription factor 4 (ATF4), a key effector of the integrated stress response. ATF4 translation is normally induced by phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) through a mechanism that requires upstream open reading frames (uORFs) in the ATF4 5' UTR. mTORC1 also controls ATF4 translation through uORFs, but independent of changes in eIF2α phosphorylation. mTORC1 instead employs the 4E-binding protein (4E-BP) family of translation repressors. These results link mTORC1-regulated demand for protein synthesis with an ATF4-regulated transcriptional program that controls the supply of amino acids to the translation machinery.

2017-04-15 | GSE97384 | GEO

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation

Project description:Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.

2023-06-19 | GSE179510 | GEO

Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS low Q]

Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.

2017-12-30 | GSE81643 | GEO

Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS high Q]

2017-12-30 | GSE81642 | GEO

Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [low versus high Q]

2017-12-30 | GSE81641 | GEO

Translational control through differential ribosome pausing during amino acid limitation in mammalian cells

Project description:Limitation for amino acids is thought to regulate translation in mammalian cells primarily by signaling through the kinases mTORC1 and GCN2. We find that limitation for the amino acid arginine causes a selective loss of tRNA charging, which regulates translation through ribosome pausing at two of six arginine codons. Interestingly, limitation for leucine, an essential and abundant amino acid in protein, results in little or no ribosome pausing. Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation led to loss of arginine tRNA charging and ribosome pausing. Codon-specific ribosome pausing decreased protein production and triggered premature ribosome termination without significantly reducing mRNA levels. Together, our results suggest that amino acids which are not optimally sensed by the mTORC1 and GCN2 pathways still regulate translation through an evolutionarily conserved mechanism based on synonymous codon usage.

2018-07-19 | GSE113751 | GEO

FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1

Project description:The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis via insulin, growth factors, and oncogenic signals. mTORC1 activates anabolic pathways by inducing posttranslational modifications of metabolic enzymes, and by regulating expression through transcription and mRNA processing. However, mechanisms of how mTORC1 orchestrates these tightly connected processes remain unclear. Here, we identify FAM120A as a transcriptional co-activator that couples transcription and splicing of lipid synthesis enzymes downstream of mTORC1-SRPK2 signaling. Mechanistically, the mTORC1-activated SRPK2 phosphorylates a splicing factor SRSF1, enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging newly transcribed lipogenic genes to the RNA splicing machinery. This multi-protein complex regulated by mTORC1 promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.

2023-09-01 | GSE229657 | GEO

Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome

Project description:Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

2023-11-15 | GSE247576 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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