Ontology highlight
ABSTRACT:
PROVIDER: PRJNA858446 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20167171_1.fastq.gz | Fastqsanger.gz | |||
| SRR20167171_2.fastq.gz | Fastqsanger.gz | |||
| SRR20167172_1.fastq.gz | Fastqsanger.gz | |||
| SRR20167172_2.fastq.gz | Fastqsanger.gz | |||
| SRR20167173_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Omics analyses of a somatic Trp53R245W/+ breast cancer model identify cooperating driver events activating PI3K/Akt/mTOR signaling
| PRJNA856307 | ENA
Project description:Alterations of the tumor suppressor TP53, one of the most common events in cancer, alone are insufficient for tumor development but serve as drivers of transformation. We sought to identify cooperating events through genomic analyses of a novel somatic Trp53R245W mouse model (equivalent to the TP53R248W hot spot mutation in human cancers) that recapitulates metastatic breast cancer development. We identified cooperating lesions similar to those found in human breast cancers. Moreover, we identified activation of the Pi3k/Akt/mTOR pathway in most tumors via mutations in Pten, Erbb2, Kras and/or a recurrent Pip5k1c mutation that stabilizes the Pip5k1c protein to activate Pi3k/Akt/mTOR signaling. Another PIP5K1C family member, PIP5K1A, is co-amplified with PI4KB in 18% of human breast cancer patients and both encode kinases that are responsible for production of the PI3K substrate, phosphatidylinositol 4,5-bisphosphate. Thus, the TP53R248W mutation and PI3K/Akt/mTOR signaling are major cooperative events driving breast cancer development. Additionally, we demonstrated that the upregulation of oxidative phosphorylation by Pi3k/Akt/mTOR signaling is a vulnerability in murine as well as human breast cancer cell lines. These findings advance our understanding of mutant p53-driven breast tumors and expand testable targets for breast cancer treatment.
2022-10-01 | GSE207604 | GEO
Project description:Copy number alterations are crucial for the development of gastric cancer (GC). Here, we identified Transmembrane Protein 65 (TMEM65) amplification by genomic hybridization microarray to profile copy-number variations in GC. TMEM65 mRNA level was significantly up-regulated in GC compared to adjacent normal tissues, and was positively associated with TMEM65 amplification. High TMEM65 expression or DNA copy number predicts poor prognosis in GC. Furtherly, GC patients with TMEM65 amplification or overexpression significantly associated with shortened survival. Ectopic expression of TMEM65 significantly promoted cell proliferation, cell cycle progression and cell migration/invasion ability, but inhibited apoptosis. Conversely, silencing of TMEM65 in GC cells showed opposite abilities on cell function in vitro and suppressed tumor growth and lung metastasis in vitro. Moreover, TMEM65 depletion by VNP-encapsulated TMEM65-siRNA significantly suppressed tumor growth in subcutaneous xenograft model. Mechanistically, TMEM65 exerted oncogenic effects through activating PI3K-Akt-mTOR signaling pathway, as evidenced of increased expression of key regulators (p-Akt, p-GSK-3β, p-mTOR) by Western blot. YWHAZ (Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase) was identified as a direct downstream effector of TMEM65. Direct binding of TMEM65 with YWHAZ in the cytoplasm inhibited ubiquitin-mediated degradation of YWHAZ. Moreover, oncogenic effect of TMEM65 was partly dependent on YWHAZ. In conclusion, TMEM65 promotes gastric tumorigenesis by activating PI3K-Akt-mTOR signaling via cooperating with YWHAZ. TMEM65 overexpression may serve as an independent new biomarker and is a therapeutic target in GC.
2024-01-26 | GSE254012 | GEO
Project description:Lck-MyrAkt2 mice develop spontaneous thymic lymphomas at approximately 100-200 days of age, driven in part by a consitutatively-active AKT (due to myristoylation). mTOR Knock Down mice were crossed with Lck-MyrAkt postive mice to model the affects of decreasing mTOR activity on tumors with an activated PI3K/AKT/MTOR pathway. Lck-Akt/mTOR KD mice had prolonged survival compared to the Lck-Akt/mTOR WT mice. We used microarrays to compare the transcriptome in thymic lymphomas between Lck-Akt positive, mTOR WT and Lck-Akt positive, mTOR KD mice. Four thymic lymphomas from Lck-Akt/mTOR WT mice were compared to three thymic lymphomas from Lck-Akt/mTOR KD mice.
2015-09-15 | E-MTAB-3242 | biostudies-arrayexpress
Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT
The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H).
This model is described in the article:
Computational Modelling of the Metabolic States Regulated by the Kinase Akt.
Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Frontiers in Systems Biology. 2012 Oct 13
Abstract:
Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.
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2024-09-02 | BIOMD0000000426 | BioModels
Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound. Global RNA expression in primary cells from two MCL patients treated with a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor for 8 hours
2013-12-14 | E-GEOD-53309 | biostudies-arrayexpress
Project description:High activation of the PI3K-AKT-mTOR pathway is characteristic for T-cell acute lymphoblastic leukemia (T-ALL). Here we investigated how 4EGI-1, a small inhibitor of cap-dependent translation, induces apoptosis in T-ALL clones displaying hyperactive PI3K-AKT-mTOR signaling. 4EGI-1 treatment reduced the ribosomal occupancy of transcripts that define the molecular difference between T-ALL blasts and normal thymocytes. These transcripts encoded proteins for the translational machinery, for mitochondrial metabolism as well as oncoproteins such as Cyclin D1, Bcl-2 and c-myc. Therefore, targeting translation initiation proves valuable in situations where mTOR is activated by multiple events.
2014-01-01 | GSE41382 | GEO
Project description:High activation of the PI3K-AKT-mTOR pathway is characteristic for T-cell acute lymphoblastic leukemia (T-ALL). Here we investigated how 4EGI-1, a small inhibitor of cap-dependent translation, induces apoptosis in T-ALL clones displaying hyperactive PI3K-AKT-mTOR signaling. 4EGI-1 treatment reduced the ribosomal occupancy of transcripts that define the molecular difference between T-ALL blasts and normal thymocytes. These transcripts encoded proteins for the translational machinery, for mitochondrial metabolism as well as oncoproteins such as Cyclin D1, Bcl-2 and c-myc. Therefore, targeting translation initiation proves valuable in situations where mTOR is activated by multiple events.
2015-02-01 | GSE56150 | GEO
Project description:Purpose: The PI3K/AKT/mTOR pathway is activated in most MM. In MM the mechanism of this pathway activation has not been completely elucidated, although loss of expression of PI3K pathway regulator, PTEN, is a frequent event in MM. Pten;Trp53 combined genetic loss in mouse mesothelium leads to non-epithelioid MM development. We assessed more broadly the impact of PI3K activation in MM development by comparing the effects of Pik3ca activation versus Pten inactivation in combination with Trp53 deletion on MM development. RNAseq was performed from tumor samples derived from Ptenlox/lox ; Trp53lox/lox and Pik3caH1047R/+; Trp53lox/lox mice derived sarcomatoid MM. Results: Our data also reveal that Pten loss has stronger oncogenic properties than Pik3ca mutation in MM.
2019-12-10 | GSE138389 | GEO
Project description:Mucin 3A(MUC3A) is overexpressed in colorectal cancer (CRC) and associated with poor prognosis, but the related mechanism remains unclear. Our study found that MUC3A promotes the progression of CRC by activating the PI3K/Akt/mTOR signaling pathway. Knockout of MUC3A significantly inhibited the proliferation of CRC cells and induced G1 phase arrest by upregulating p21 protein, an important cell cycle regulator. Moreover, knockout of MUC3A significantly inhibited invasion ability and enhanced the sensitivity to the chemotherapeutic agent 5-FU. Furthermore, we found that knockout of MUC3A repressed the PI3K/Akt/mTOR pathway through RNA-seq. Treatment with the PI3K/Akt/mTOR pathway inhibitor rapamycin successfully eliminated the difference in proliferation, invasion and chemoresistance between MUC3A knockout cells and control cells. Our study suggests that MUC3A is a potential oncogene that promotes the proliferation, invasion, and chemotherapy resistance of CRC. Moreover, CRC patients with high expression of MUC3A may benefit from rapamycin treatment.
2022-04-23 | GSE201107 | GEO