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Expression data from control and Phospholipid dependent kinase 1 (PDK1) null cytotoxic T-lymphocytes (CTL) and from control and Akt inhibitor treated CTL

ABSTRACT: In cytotoxic T cells (CTL), Protein Kinase B /Akt is activated by the T cell antigen receptor (TCR) and the cytokine Interleukin 2 (IL2), in part by phosophorylation of Akt by Phospholipid dependent kinase 1 (PDK1). The role of PDK1 and Akt in CTL has however not been fully defined. In order to explore the relative roles of these kinases in CTL we used microarrays to profile the gene expression of control and PDK1 null CTL. In separate experiments we compared the gene expression profiles of control and Akt inhibitor treated CTL.

ORGANISM(S): Mus musculus

PROVIDER: GSE26290 | GEO | 2011/02/01

SECONDARY ACCESSION(S): PRJNA135051

REPOSITORIES: GEO

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Expression data from control and Phospholipid dependent kinase 1 (PDK1) null cytotoxic T-lymphocytes (CTL) and from control and Akt inhibitor treated CTL

Project description:In cytotoxic T cells (CTL), Protein Kinase B /Akt is activated by the T cell antigen receptor (TCR) and the cytokine Interleukin 2 (IL2), in part by phosophorylation of Akt by Phospholipid dependent kinase 1 (PDK1). The role of PDK1 and Akt in CTL has however not been fully defined. In order to explore the relative roles of these kinases in CTL we used microarrays to profile the gene expression of control and PDK1 null CTL. In separate experiments we compared the gene expression profiles of control and Akt inhibitor treated CTL. CTL were generated from 3 mice each carrying two loxP flanked PDK1 alleles plus a tamoxifen inducible Cre transgene. PDK1 was then deleted from these CTL by tamoxifen treatment and the gene expression pattern determined by microarray. Tamoxifen treated PDK1wt/wt TamoxCre+ CTL generated from 3 PDK1wt/wt TamocCre+ mice were used as a control. In separate experiments CTL were were generated from 3 wild-type mice and then half the CTL generated from each mouse were treated with the Akt inhibitor AktI-1/2. The gene expression patterns of the AktI treated and the untreated CTL were then compared by microarray.

2011-02-01 | E-GEOD-26290 | biostudies-arrayexpress

S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions

Project description:Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.

2021-08-27 | PXD028167 | iProX

PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to mTOR-targeted Therapy.

Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K

2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress

Hydrogen Deuterium Exchange of PDK1

Project description:This project consisted of three HDX-MS experiments. First, we compared the dimeric PDK1(SKD-PIF) to monomeric PDK1(SKD) and mapped the differences in deuterium incorporation onto the dimer model. We then compared the deuterium incorporation kinetics for the kinase (PDK1(SKD)) and PH (PDK1(PH) domains of PDK1 with full-length PDK1 (PDK1(FL)) in pairwise experiments.

2022-05-20 | PXD027401 | Pride

Mus musculus

Project description:Expression data from control and Phospholipid dependent kinase 1 (PDK1) null cytotoxic T-lymphocytes (CTL) and from control and Akt inhibitor treated CTL

| PRJNA135051 | ENA

PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to mTOR-targeted Therapy.

2013-07-31 | GSE30669 | GEO

Effect of rapamycin and KU-0063794 on CTL gene expression

Project description:Comparison of transcriptional profile of CD8 cytotoxic T lymphocytes terated with the mTORC1 inhibitor rapamycin or the mTOR inhibitor KU-0063794 and comparison with proteomic analysis. Abstract: High resolution mass spectrometry maps the cytotoxic T lymphocyte (CTL) proteome and the impact of mammalian target of rapamycin complex 1 (mTORC1) on CTL. We show that the CTL proteome is dominated by metabolic regulators and granzymes and that mTORC1 selectively represses and promotes expression of a protein subset (~10%) including key CTL effector molecules and signaling proteins. mTORC1 also controlled flux through a subset of metabolic pathways rather than acting as an on/off switch for global CTL metabolism. Proteomic data highlighted the potential for mTORC1 negative control of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production in CTL. Further work revealed that mTORC1 represses PIP3 production and determines the mTORC2 requirement for activation of the serine/threonine kinase AKT. Unbiased proteomic analysis thus provides a comprehensive understanding of CTL identity and mTORC1 control of CTL function.

2015-07-15 | GSE70925 | GEO

Claspin is required for growth recovery from serum starvation through regulating the PI3K-PDK1-mTOR pathway

Project description:Growth recovery from serum starvation requires the activation of PI3 kinase (PI3K)- PDK1-Akt-mTOR pathways. Claspin plays multiple important roles in regulation of DNA replication as a mediator for the cellular response to replication stress, an integral replication fork factor that facilitates replication fork progression and a factor that promotes initiation by recruiting Cdc7 kinase. Here, we report a novel role of Claspin in growth recovery from serum starvation. In the absence of Claspin, cells do not proceed into S phase and eventually die. Claspin interacts with PI3K and mTOR, and is required for activation of PI3K-PDK1-mTOR and for that of mTOR downstream factors, p70S6K and 4E-BP1, but not for p38 MAPK cascade during the recovery from serum starvation. PDK1 interacts with Claspin, notably with CKBD, in a manner dependent on phosphorylation of the latter protein, and is required for interaction of mTOR with Claspin. p53 and ROS (Reactive Oxygen Species) inhibitors increased survival of Claspin-deficient cells released from serum starvation. Thus, Claspin plays a novel role as a mediator/protein platform for nutrition-induced proliferation/survival signaling by activating the mTOR pathway.

2022-04-15 | GSE200669 | GEO

Role of PDK1 in Skeletal Muscle Hypertrophy Induced by Exercise Load

Project description:Skeletal muscle mass is an important determinant of whole-body glucose disposal. We here show that mice (M-PDK1KO mice) with skeletal muscle–specific deficiency of 3'-phosphoinositide–dependent kinase 1 (PDK1), a key component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of exercise load–induced muscle hypertrophy. Whereas exercise load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by exercise load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of protein synthesis via the S6K-S6 axis.

2020-05-14 | GSE150464 | GEO

Expression data from MMTV-PDK1 transgenic mice

Project description:The role of PDK1 on mammary tumorigenesis and its interaction with PPARdelta, was assessed. Transgenic mice were generated in which PDK1 was expressed in the mammary epithelium. We used microarrays to analyse global gene expression changes in MMTV-PDK1 transgenic mice versus wild-type mice and determine any differential responses to GW501516 treatment.

2011-02-05 | GSE27083 | GEO

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