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Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

ABSTRACT: Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

ORGANISM(S): Mus musculus

PROVIDER: GSE66177 | GEO | 2015/02/24

SECONDARY ACCESSION(S): PRJNA276065

REPOSITORIES: GEO

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Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Project description:Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. 5 different experimental conditions were compared (including GFP, PDGFB, PDGFB in conjunciton with Akt1, Akt2, or Akt3) with 3 mice per treatment

2015-02-24 | E-GEOD-66177 | biostudies-arrayexpress

AKTs do not translocate to the nucleus upon stimulation but AKT3 can constitutively signal from the nuclear envelope

Project description:Unlike other signaling proteins, cellular stimulation does not induce nuclear AKT accumulation. While AKT1 is cytoplasmic, shifting to the plasma membrane upon stimulation, AKT2 is mainly nuclear. AKT3 in cancer cells is constitutively active at the nuclear envelope, where it phosphorylates TSC2 and promotes proliferation.

2022-12-11 | PXD037856 | Pride

Effect of cardiomyocyte specific KO of AKT1, AKT2, and AKT1 + AKT2 on gene expression profile of the heart

Project description:In the mammalian heart AKT1 and AKT2 are the isoforms of the protein kinase AKT (protein kinase B) which are predominantly expressed. AKT isoforms exert common and specific functions in the field of metabolism, cellular growth, apoptosis and cell migration. To identify specific and common functions of AKT1 and AKT2 isoforms, we generated tamoxifen-inducible, cardiomyocyte-specific AKT1, AKT2, and AKT1+AKT2 double knockout mice (iCMAKT – KO mice). Inactivation of AKT isoforms was achieved by application of 4-OH-tamoxifen, which activates an OH-Tx inducible cre-recombinase expressed under the control of the αMHC-promoter (αMHC-mercremer). Transgenic mice expressing only the αMHCmercremer construct were also treated with OH-Tx and served as controls. To identify alterations in cardiac gene expression due to AKT deletion we analyzed gene expression profiles of control hearts, iCMAKT1, iCMAKT2 and iCMAKT1+2 hearts.

2017-11-30 | GSE86231 | GEO

Gene expression analysis of Akt2 deficient murine naive CD4 T cells cultured in Th17-polarizing conditions for 36 hours

Project description:Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than Akt1. To better understand the consequences of Akt2 deficiency in the setting of in vitro Th17 differentiation, we used microarray analysis to compare the transcriptional landscape of Akt2â/â and WT cells that had been cultured in Th17 polarizing conditions for 36 hours.

2016-07-03 | E-MTAB-4062 | biostudies-arrayexpress

Mus musculus

Project description:Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

| PRJNA276065 | ENA

Effect of cardiomyocyte specific KO of AKT1 + AKT2 on gene expression profile of the heart

Project description:In the mammalian heart AKT1 and AKT2 are the isoforms of the protein kinase AKT (protein kinase B) which are predominantly expressed. AKT isoforms exert common and specific functions in the field of metabolism, cellular growth, apoptosis and cell migration. To identify specific and common functions of AKT1 and AKT2 isoforms, we generated tamoxifen-inducible, cardiomyocyte-specific AKT1+AKT2 double knockout mice (iCMAKT – KO mice). Inactivation of AKT isoforms was achieved by application of 4-OH-tamoxifen, which activates an OH-Tx inducible cre-recombinase expressed under the control of the αMHC-promoter (αMHC-mercremer). Transgenic mice expressing only the αMHCmercremer construct were also treated with OH-Tx and served as controls. To identify alterations in cardiac gene expression due to AKT deletion we analyzed gene expression profiles of control hearts and iCMAKT1+2 hearts.

2017-11-30 | GSE86230 | GEO

Akt2 partners L6 myoblasts - Novel Endogenous, Insulin-Stimulated Akt2 Protein Interaction Partners in L6 Myoblasts

Project description:Insulin resistance and Type 2 diabetes are marked by an aberrant response in the insulin signaling network. The phosphoinositide-dependent serine/threonine kinase, Akt2, plays a key role in insulin signaling and glucose uptake, most notably within skeletal muscle. Protein-protein interaction regulates the functional consequence of Akt2 and in turn, Akt2’s role in glucose uptake. However, only few insulin-responsive Akt2 interaction partners have been identified in skeletal muscle cells. In the present work, rat L6 myoblasts, a widely used insulin sensitive skeletal muscle cell line, were used to examine endogenous, insulin-stimulated Akt2 protein interaction partners. Akt2 co-immunoprecipitation was coupled with 1D-SDS-PAGE and fractions were analyzed by HPLC-ESI-MS/MS to reveal Akt2 protein-protein interactions. The pull-down assay displayed specificity for the Akt2 isoform; Akt1 and Akt3 unique peptides were not detected. A total of 330 proteins were significantly enriched as bonafide Akt2 protein interaction partners. Among them, 226 were novel for any cell types. Furthermore, 59 were detected with a significantly increased (57) or decreased (2) association with Akt2 following insulin administration (n=4; p<0.05). Multiple pathways were identified for the novel Akt2 interaction partners, such as the EIF2 and ubiquitination pathways. These data suggest that multiple new endogenous proteins may associate with Akt2 under basal as well as insulin-stimulated conditions, providing further insight into the insulin signaling network.

2015-09-30 | PXD002557 | Pride

AKT Isoform Specificity Downstream of PIK3CA Mutation Impacts Estradiol and PI3K Inhibitor Response in Breast Cancer Cells

Project description:Background: PIK3CA mutations are observed in >30% of breast cancers, which are more common in estrogen receptor (ERα)-positive breast cancer compared with ERα-negative breast cancer. AKT1, 2, and 3 isoforms, major isoforms downstream of PI3K, modulate ERα activity. It is unknown whether PIK3CA mutation leads to preferential activation of specific AKT isoforms with an ability to modulate ERα function. Methods: Gene expression arrays were performed on parental, AKT1 knockdown or AKT2 knockdown MCF-7 breast cancer cells with or without estradiol treatment for three hours. Results: AKT1 had a dominant role in ERα:estradiol-dependent gene expression and proliferation. We have identified a unique gene expression signature that is dependent on ERα, estradiol, AKT1 and the pioneer factor FOXA1. Overexpression of this signature was associated with better outcome in patients with ERα-positive breast cancer. In contrast, AKT2 controlled global gene expression.

2016-08-10 | GSE60759 | GEO

PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression

Project description:PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastatic development: Pten/RbPE:-/- mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:-/- mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node dissemination, correlating with upregulated phosphotyrosyl PI3K-p85α. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110β and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110α plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways.

2023-11-01 | GSE242387 | GEO

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns hypomethylation patterns

Project description:Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG present specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450k or 850k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labelled “Wild type-C” or “Paediatric RTK 1”. Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.

2020-11-02 | GSE157397 | GEO

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