Gene expression analysis of Akt2 deficient murine naive CD4 T cells cultured in Th17-polarizing conditions for 36 hours
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Lauren Banks
PROVIDER: E-MTAB-4062 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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2017-11-30 | GSE86231 | GEO
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.
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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.
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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
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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.
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