Molecular characterization of BRSK2 and BRSK1 kinases as negative regulators of the NRF2 transcription factor
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE139135 | GEO | 2019/11/16
REPOSITORIES: GEO
Similar Datasets
Project description:NFE2L2/NRF2 is a transcription factor and master regulator of the cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, resulting in increased cellular fitness, chemo-radiation resistance, metabolic reprogramming and immune evasion. NRF2 protein levels and activity is governed primarily by the KEAP1/CUL3 ubiquitin ligase and subsequent proteasomal degradation. To what extent parallel signaling pathways and protein classes impact NRF2 activity remains to be fully explored. Also, because NRF2-directed therapies remain in the discovery and early development stages, continued identification and validation of NRF2 regulators is of potential clinical value. Here we used a gain-of-function genetic screen of the kinome to identify druggable activators and inhibitors of NRF2 signaling. We found that the understudied Brain Selective Kinase 1 and 2 (BRSK1/2) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phospho-proteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK1/2-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Strategies which exploit these relationships may prove useful for therapeutically targeting NRF2 in cancer.
2020-06-24 | PXD015884 | Pride
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 2)
This
model is as described in the Supplementary Software 2 of the
reference publication:
SBML
model including four amino acids input in the network (simple
p70-S6K module).
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
MODEL1705030001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1705030001 | BioModels
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 3)
This model is as described in
the Supplementary Software 3 of the reference publication: SBML
model similar to Model S2, but including a more complex p70-S6K
module.
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000640.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-05-07 | BIOMD0000000640 | BioModels
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 1)
This model is as described in
Supplementary Software 2 of the reference publication:
SBML
model including only the canonical amino acid input on
mTORC1.
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
MODEL1705030000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1705030000 | BioModels
Project description:WGS and RNA-seq data for Nrf2 study
| EGAS00001001740 | EGA
Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.
2014-02-18 | E-GEOD-55001 | biostudies-arrayexpress
Project description:Liver tumors had high levels of histone acetylation. Nrf2 knockout mice developed fewer tumors than Nrf2 wild-type mice. The mechanistic study found that Nrf2 knockout reduced the generation of acetyl CoA from impaired glycolysis, TCA cycle, and fatty acid metabolism. Acetyl CoA is the substrate for protein acetylation including histone acetylation. Here we determined the genome-wide distribution of AcH3K27. We found that Nrf2 through regulating acetyl CoA production affects histone acetylation (AcH3K27) to modulate the expression of genes, whose products were involved in the glycolysis, TCA cycle, fatty acid metabolism, and oncogenic Myc/mTor signaling. Our findings supported an Nrf2-integrated metabolic, epigenetic and oncogenic signaling in driving liver tumor development.
2023-03-20 | GSE227068 | GEO
Project description:Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.
2016-12-12 | PXD003073 | Pride
Project description:Sonntag2012 - mTOR model - IRS dependent regulation of AMPK by insulin
TSC1-TSC2 complex has two states: 1)
active (TSC1_TSC2_pS1387), regulated by AMPK_pT172; 2) inactive
(TSC1_TSC2_pT1462) regulated by Akt_pT308. Particularly, mTORC1 is
inhibited by TSC1_TSC2 in active state. AMPK is activated at T172
by the species IRS1_p activated by the insulin receptor upon
insulin stimulation. Consequently, AMPK_pT172 is inhibited by
mTORC1_pS2448 indirectly by the p70-S6K-negative feedback loop.
This model is described in the article:
A modelling-experimental
approach reveals insulin receptor substrate (IRS)-dependent
regulation of adenosine monosphosphate-dependent kinase (AMPK)
by insulin.
Sonntag AG, Dalle Pezze P, Shanley
DP, Thedieck K.
FEBS J. 2012 Sep; 279(18):
3314-3328
Abstract:
Mammalian target of rapamycin (mTOR) kinase responds to
growth factors, nutrients and cellular energy status and is a
central controller of cellular growth. mTOR exists in two
multiprotein complexes that are embedded into a complex
signalling network. Adenosine monophosphate-dependent kinase
(AMPK) is activated by energy deprivation and shuts off
adenosine 5'-triphosphate (ATP)-consuming anabolic processes,
in part via the inactivation of mTORC1. Surprisingly, we
observed that AMPK not only responds to energy deprivation but
can also be activated by insulin, and is further induced in
mTORC1-deficient cells. We have recently modelled the mTOR
network, covering both mTOR complexes and their insulin and
nutrient inputs. In the present study we extended the network
by an AMPK module to generate the to date most comprehensive
data-driven dynamic AMPK-mTOR network model. In order to define
the intersection via which AMPK is activated by the insulin
network, we compared simulations for six different hypothetical
model structures to our observed AMPK dynamics. Hypotheses
ranking suggested that the most probable intersection between
insulin and AMPK was the insulin receptor substrate (IRS) and
that the effects of canonical IRS downstream cues on AMPK would
be mediated via an mTORC1-driven negative-feedback loop. We
tested these predictions experimentally in multiple set-ups,
where we inhibited or induced players along the insulin-mTORC1
signalling axis and observed AMPK induction or inhibition. We
confirmed the identified model and therefore report a novel
connection within the insulin-mTOR-AMPK network: we conclude
that AMPK is positively regulated by IRS and can be inhibited
via the negative-feedback loop.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000580.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-08-12 | BIOMD0000000580 | BioModels
Project description:Results: Prenatal SUL altered baseline lung genes involved in organ/cell development and grow (e.g., Ibsp, Ctsk, Igfbp5) and ARE responses (e.g., Aldh3a1, Maff, Mafg) in Nrf2+/+ neonates and in cell morphogenesis and cell death and organismal injury/abnormality inhibition (e.g., Neat1, Nox4, Vegfa, Igfbp2, Trp53) in Nrf2-/- neonates. In hyperoxia-exposed lung, prenatal SULincreased organogenesis/development genes (e.g., Prss35, Cep128) and decreased inflammatory genes (H2-D1, Cd40, Lcn2, Cdh22) in Nrf2+/+ pups. In Nrf2-/- mice exposed to hyperoxia, prenatal SFN decreased hyperoxia-upregulated many immune and inflammatory response genes (e.g., Ccl9, Btla, Ncf4, Ltb, Selplg, Csf2rb) and upregulated many DNA repair/damage checkpoint genes (e.g., Uimc1, Neil3, Nbn, Smc4, Smc6). Conclusion: Overall, prenatal maternal SUL altered genes differentially in Nrf2+/+ and Nrf2-/- lungs. However, SUL-mediated transcriptome changes affected similar biological functions benificial to host defense and organ development in both strain. Compensatory differential lung transcriptome changes in Nrf2-/- neonates may resulted in the manifest protection of their severe hyperoxic lung injury.
2022-01-05 | GSE164699 | GEO