TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1153513 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30463116_1.fastq.gz | Fastqsanger.gz | |||
| SRR30463116_2.fastq.gz | Fastqsanger.gz | |||
| SRR30463117_1.fastq.gz | Fastqsanger.gz | |||
| SRR30463117_2.fastq.gz | Fastqsanger.gz | |||
| SRR30463118_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC is a key molecular event in HCC. In this study, we explored the roles of TSC/mTORC1 and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had minimal impact on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablating TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E act downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.
2024-09-15 | GSE275889 | GEO
Project description:Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC is a key molecular event in HCC. In this study, we explored the roles of TSC/mTORC1 and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had minimal impact on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablating TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E act downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.
2024-09-15 | GSE276215 | GEO
Project description:TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M
| PRJNA1155993 | ENA
Project description:DallePezze2012 - TSC-independent mTORC2
regulation
This model is described in the article:
A dynamic network model of
mTOR signaling reveals TSC-independent mTORC2 regulation.
Dalle Pezze P, Sonntag AG, Thien A,
Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber
TB, Baumeister R, Shanley DP, Thedieck K.
Sci Signal 2012 Mar; 5(217): ra25
Abstract:
The kinase mammalian target of rapamycin (mTOR) exists in
two multiprotein complexes (mTORC1 and mTORC2) and is a central
regulator of growth and metabolism. Insulin activation of
mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and
the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2),
initiates a negative feedback loop that ultimately inhibits
PI3K. We present a data-driven dynamic insulin-mTOR network
model that integrates the entire core network and used this
model to investigate the less well understood mechanisms by
which insulin regulates mTORC2. By analyzing the effects of
perturbations targeting several levels within the network in
silico and experimentally, we found that, in contrast to
current hypotheses, the TSC1-TSC2 complex was not a direct or
indirect (acting through the negative feedback loop) regulator
of mTORC2. Although mTORC2 activation required active PI3K,
this was not affected by the negative feedback loop. Therefore,
we propose an mTORC2 activation pathway through a PI3K variant
that is insensitive to the negative feedback loop that
regulates mTORC1. This putative pathway predicts that mTORC2
would be refractory to Akt, which inhibits TSC1-TSC2, and,
indeed, we found that mTORC2 was insensitive to constitutive
Akt activation in several cell types. Our results suggest that
a previously unknown network structure connects mTORC2 to its
upstream cues and clarifies which molecular connectors
contribute to mTORC2 activation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000581.
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.
2024-09-02 | BIOMD0000000581 | BioModels
Project description:MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e, miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4) whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signalling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1-/- macrophages exhibited increased responsiveness to LPS in culture and Akt1-/- mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1-/- macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression. The data deposited here contain the entire analysis of miRNA profile of Akt1+/+ and Akt1-/- thioglycollate elicited peritoneal macrophages following stimulation with LPS for 3 hours in culture.
2009-08-21 | GSE17421 | GEO
Project description:Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with limited treatment options. The c-Myc transcription factor is a pivotal player in hepatocarcinogenesis, but the mechanisms underlying c-Myc oncogenic activity in the liver remain poorly delineated. Mammalian target of rapamycin complex 2 (mTORC2) has been implicated in cancer by regulating multiple AGC kinases, especially AKT proteins. In the liver, AKT1 and AKT2 are widely expressed. While AKT2 is the major isoform downstream of activated phosphoinositide 3-kinase and loss of phosphatase and tensin homolog-induced HCC, the precise function of AKT1 in hepatocarcinogenesis is largely unknown. In the present study, we demonstrate that mTORC2 is activated in c-Myc-driven mouse HCC, leading to phosphorylation/activation of Akt1 but not Akt2. Ablation of Rictor inhibited c-Myc-induced HCC formation in vivo. Mechanistically, we discovered that loss of Akt1, but not Akt2, completely prevented c-Myc HCC formation in mice. Silencing of Rictor or Akt1 in c-Myc HCC cell lines inhibited phosphorylated forkhead box o1 expression and strongly suppressed cell growth in vitro. In human HCC samples, c-MYC activation is strongly correlated with phosphorylated AKT1 expression. Higher expression of RICTOR and AKT1, but not AKT2, is associated with poor survival of patients with HCC. In c-Myc mice, while rapamycin, an mTORC1 inhibitor, had limited efficacy at preventing c-Myc-driven HCC progression, the dual mTORC1 and mTORC2 inhibitor MLN0128 effectively promoted tumor regression by inducing apoptosis and necrosis. Conclusion: Our study indicates the functional contribution of mTORC2/Akt1 along c-Myc-induced hepatocarcinogenesis, with AKT1 and AKT2 having distinct roles in HCC development and progression; targeting both mTORC1 and mTORC2 may be required for effective treatment of human HCC displaying c-Myc amplification or overexpression.
| S-EPMC7195156 | biostudies-literature
Project description:MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e, miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4) whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signalling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1-/- macrophages exhibited increased responsiveness to LPS in culture and Akt1-/- mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1-/- macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression. The data deposited here contain the entire analysis of miRNA profile of Akt1+/+ and Akt1-/- thioglycollate elicited peritoneal macrophages following stimulation with LPS for 3 hours in culture. Thioglycollate elicited macrophages were cultured in complete DMEM medium, stimulated with LPS for 3 hours and RNA was extracted. Samples were analyzed using Taq-man PCR miRNA arrays (Dana Farber microarray Facility).
2009-08-21 | E-GEOD-17421 | biostudies-arrayexpress
Project description:Genome wide DNA methylation profiling of control and mTORC2-suppressed glioblastoma cells (U87-EGFRvIII cells). The Illumina Infinium HumanMethylation EPIC BeadChip Array was used to obtain DNA methylation profiles with 865,918 probes in glioblastoma cell line samples. Samples included 2 control U87-MG cells without mTORC2 suppresion, and mTORC2-knockdown U87-MG cells with lentivirus-mediated suppression of mTORC2.
2024-03-20 | GSE235207 | GEO
Project description:To screen miRNAs specifically regulated by mTORC1 or mTORC2, a global miRNA expression profile in MCF-7 cells treated with rapamycin or PP242 (mTORC1/2 kinase inhibitor) was developed using microarray. control, rapamycin or PP242 treated human MCF-7 cells were harvested 48h post-treatment and subjected to total RNA extraction.
2014-09-11 | E-GEOD-61289 | biostudies-arrayexpress
Project description:AKT1 is a serine/threonine kinase implicated in fetal, placental, and postnatal growth. In this study, we investigated roles for AKT1 in placental development using a genome-edited/loss-of-function rat model. Both heterozygous and homozygous Akt1 mutant rats were viable and fertile. Disruption of AKT1 resulted in placental, fetal, and postnatal growth restriction. Akt1 null placentas showed deficits in both junctional zone and labyrinth zone size and their ability to adapt to a physiological stressor. Robust differences in the transcriptome of wild type versus Akt1 null junctional zones were identified. Among the differentially expressed junctional zone transcripts was forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate. FOXO4 expression was prominent in the junctional zone and invasive trophoblast cells of the rat placentation site and enhanced following rat TS cell differentiation. Foxo4 gene disruption using genome-editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells; however, in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network controlling hemochorial placenta development.
2023-01-05 | GSE205829 | GEO