C-tail hyperphosphorylation activates PTEN oncogenic properties
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA849506 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19661836_1.fastq.gz | Fastqsanger.gz | |||
| SRR19661836_2.fastq.gz | Fastqsanger.gz | |||
| SRR19661837_1.fastq.gz | Fastqsanger.gz | |||
| SRR19661837_2.fastq.gz | Fastqsanger.gz | |||
| SRR19661838_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 18 |
Similar Datasets
Project description:PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumor suppression remains unknown. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a C-tail residue hyperphosphorylated in human gastric cancers, reveals that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyper-phosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.
2023-04-17 | GSE206157 | GEO
Project description:To investigate the effects of PTEN activity on gene expression in 3D cultured glioblastoma cells and the contributions of PTEN's lipid and protein phosphatase activities to these effects. We expressed wild type PTEN, a catalytically dead mutant (C124S) or mutants selectively lacking protein or lipid phosphatase activity (Y138L and G129E respectively) in U87MG cells at physiological levels by transient unselected polyclonal lentiviral transduction. Cells were then seeded into 3D matrigel and RNA prepared after 15 hours.
2012-02-28 | E-MTAB-989 | biostudies-arrayexpress
Project description:The PTEN:P-Rex2 complex is a commonly mutated signaling nodes in metastatic cancer. The dual-specificity phosphatase PTEN canonically functions as a tumour suppressor by hydrolysing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling. P-Rex2 is a RhoGTPase guanine nucleotide exchange factor activated by both Gβγ and PI(3,4,5)P3 downstream of G protein-coupled receptor and receptor tyrosine kinase signaling. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cell proliferation. However, structural insights into both PTEN:P-Rex2 complex assembly and its dysregulation by cancer-associated mutations remain limited. Here, using crosslinking mass spectrometry and functional studies, we provide mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN C-terminal tail PDZ-interacting motif and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. In addition, we observe synergy between PTEN deactivating and P-Rex2 truncation mutations that combine to drive Rac1 activation to a greater extent than either single mutation alone.
2022-08-12 | PXD021126 | Pride
Project description:Prostate cancer (PCa) is the second leading cause of cancer death in men. Its clinical and molecular heterogeneity and the lack of in vitro models outline the complexity of PCa in the clinical and research settings. We established an in vitro mouse PCa model based on organoid technology that takes into account the cell of origin and the order of events. Primary PCa with deletion of the tumor suppressor gene PTEN (PTEN-del) can be modeled through Pten-downregulation in mouse organoids. We used this system to elucidate the contribution of TIP5 in PCa initiation, a chromatin regulator that is implicated in aggressive PCa. High TIP5 expression correlates with primary PTEN-del PCa and this combination strongly associates with reduced PSA recurrence-free survival. TIP5 is critical for the initiation of PCa of luminal origin mediated by Pten loss whereas it is dispensable once Pten-loss mediated transformation is established. Cross-species analyses revealed a PTEN gene signature that identified a group of aggressive primary PCa characterized by PTEN-deletion, high-TIP5 expression, and a TIP5-regulated gene expression profile. The results highlight the modelling of PCa with organoids as a powerful tool to elucidate the role of genetic alterations found in recent studies in their time order and cell of origin, thereby providing further optimization for tumour stratification to improve the clinical management of PCa.
2020-02-03 | GSE131845 | GEO
Project description:Decremental loss of PTEN results in cancer susceptibility and tumor progression. In turn this raises the possibility that PTEN elevation might be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with variably elevated PTEN expression levels, taking advantage of BAC (Bacterial Artificial Chromosome)-mediated transgenesis. Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake, increased mitochondrial oxidative phosphorylation, and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and independent pathways, and negatively impacts two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect. In order to elucidate the pathophysiological impact of PTEN elevation, we generated transgenic mice carrying additional copies of this critical tumor suppressor gene (referred to as Super-PTEN mice). In order to maintain the regulation properties of the endogenous Pten gene, we made use of large genomic fragments containing the entire Pten locus carried by BACs (Bacterial Artificial Chromosomes). We next generated mouse embryonic fibroblasts (MEFs) and confirmed successful overexpression of PTEN by the BAC transgenic system. Primary cells derived from Super-PTEN mice represent a powerful tool to elucidate the molecular mechanisms underlying dose-dependent PTEN actions. We therefore performed microarray analysis in primary cells (MEFs) derived from day 13.5 embryos obtained by crossing Super-PTEN mice with C57BL6 mice. Three independent embryos from each genotype were analyzed (background: >98%C57BL6 / CBA). Gene expression profile analysis in these cells will reveal target genes and pathways differentially regulated upon PTEN elevation.
2012-12-01 | E-GEOD-35670 | biostudies-arrayexpress
Project description:WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated by genetic crossing. In these mice, Pten is deleted and a R270H p53 mutation in the DNA binding domain is induced upon expression of Cre recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, various bioinformatics methods, high-throughput (HTP) FDA-drug screen as well as orthotopic injection to quantify tumor initiating cells (TICs) and tail-vein injection to identify lung-metastasis. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other modles of mouse mammary tumors 2 types of Pten deletion plus p53-R270H mutation tumors (spindle and poorly differentiated) was compared with MMTV-Neu, Spindle Pten-p53-deficient tumors, and wild-type mammary gland cells.
2015-12-15 | E-GEOD-75989 | biostudies-arrayexpress
Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:PTEN is one of the most frequently mutated tumor suppressor genes, its loss has been reported in multiple tumor types and is associated with a poor outcome. PTEN-L, as a secreted isoform of PTEN, with the ability to enter cells and inhibit tumor cell growth via inhibiting AKT mediated cell proliferation. However, the distinct effect of PTEN-L on PTEN-expression or PTEN-loss tumor cells is not known yet. Here, we identified PTEN-L treatment facilitate E0771-PTEN-null tumor cells, but not PTEN-wide-type tumor cells lung outgrowth. RNA-seq and Western blot analysis suggest PTEN-L stimulation induced PTEN-null tumor cells dormancy, namely, upregulation of dormancy markers p16 and p27, cell cycle arrest, reduced cell proliferation and chemotherapy drugs resistance. Further study suggested PTEN-L mediated p38 signaling activation play the major role for PTEN-null tumor cell dormancy. The p38 inhibitor, SB202190 significantly reversed the PTEN-L induced PTEN-null tumor cells dormancy and outgrowth in lungs. Further investigation indicated the dormant PTEN-null tumor cells could escape from immunosurveillance and thus outgrowth in lungs, as PTEN-L did not promote PTEN-null tumor cells outgrowth in lung of SCID mice. Therefore, we propose that PTEN-L protects PTEN-null tumor cells from immune attack during lung metastasis via activating dormancy related pathways. This study identified PTEN-L as an activator of PTEN-loss tumor cells dormancy, which enables the efficient seeding and outgrowth of tumor cells in metastatic niches. Overall, we highlight PTEN expression status decides the outcome of PTEN-L mediated anti-tumor therapy.
2024-05-17 | GSE246600 | GEO
Project description:Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN. Thus, 293T cells were transiently transfected with plasmid encoding Flag-tagged PTEN along with empty vector, followed by affinity purification using an anti-Flag antibody, and the bound proteins were analyzed by liquid chromatography with tandem mass spectrometry (LC−MS/MS). Here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN.
2020-04-22 | PXD017983 | Pride
Project description:We intended to elucidate the underlying mechanism of PTEN-Nedd8 in tumorigenesis. So, we firstly employed affinity purification and mass spectrometry to interrogate PTEN-Nedd8 interactome in nucleus.
2022-05-20 | PXD011395 | Pride