Dataset Information

Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by Membrane Targeting.

ABSTRACT: Phosphatidylinositol 3-kinase-related kinases (PIKKs) play vital roles in the regulation of cell growth, proliferation, survival, and consequently metabolism, as well as in the cellular response to stresses such as ionizing radiation or redox changes. In humans six family members are known to date, namely mammalian/mechanistic target of rapamycin (mTOR), ataxia-telangiectasia mutated (ATM), ataxia- and Rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), suppressor of morphogenesis in genitalia-1 (SMG-1), and transformation/transcription domain-associated protein (TRRAP). All fulfill rather diverse functions and most of them have been detected in different cellular compartments including various cellular membranes. It has been suggested that the regulation of the localization of signaling proteins allows for generating a locally specific output. Moreover, spatial partitioning is expected to improve the reliability of biochemical signaling. Since these assumptions may also be true for the regulation of PIKK function, the current knowledge about the regulation of the localization of PIKKs at different cellular (membrane) compartments by a network of interactions is reviewed. Membrane targeting can involve direct lipid-/membrane interactions as well as interactions with membrane-anchored regulatory proteins, such as, for example, small GTPases, or a combination of both.

SUBMITTER: De Cicco M

PROVIDER: S-EPMC4703999 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by Membrane Targeting.

De Cicco Maristella M Rahim Munirah S Abd MS Dames Sonja A SA

Membranes 20150929 4

Phosphatidylinositol 3-kinase-related kinases (PIKKs) play vital roles in the regulation of cell growth, proliferation, survival, and consequently metabolism, as well as in the cellular response to stresses such as ionizing radiation or redox changes. In humans six family members are known to date, namely mammalian/mechanistic target of rapamycin (mTOR), ataxia-telangiectasia mutated (ATM), ataxia- and Rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), suppressor of m ...[more]

PMID: 26426064

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Project description:BackgroundGastric cancer (GC) is one of the most common malignant tumors. Osteopontin (OPN) is thought to be closely related to the occurrence, metastasis and prognosis of many types of tumors.AimTo investigate the effects of OPN on the proliferation, invasion and migration of GC cells and its possible mechanism.MethodsThe mRNA and protein expression of OPN in the GC cells were analyzed by real-time quantitative-reverse transcription polymerase chain reaction and western blotting, and observe the effect of varying degree expression OPN on the proliferation and other behaviors of GC. Next, the effects of OPN knockdown on GC cells migration and invasion were examined. The short hairpin RNA (shRNA) and negative control shRNA targeting OPN-shRNA were transfected into the cells according to the manufacturer's instructions. Non transfected cells were classified as control in the identical transfecting process. 24 h after RNA transfection cell proliferation activity was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay, and cell invasiveness and migration were detected by Trans well assay. Meanwhile, the expression of protein kinase B (AKT), matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF) in the human GC cell lines was detected by reverse transcription polymerase chain reaction and western blotting.ResultsThe results of this study revealed that OPN mRNA and protein expression levels were highly expressed in SGC-7901 cells. OPN knockdown by specific shRNA noticeably reduced the capabilities of proliferation, invasion and migration of SGC-7901 cells. Moreover, in the experiments of investigating the underlying mechanism, results showed that OPN knockdown could down-regulated the expression of MMP-2 and VEGF, it also decreased the phosphorylation of AKT. Meanwhile, the protein expression levels of MMP-2, VEGF and phosphorylated AKT was noticeable lower than that in control group in the GC cells after they were added to phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002).ConclusionThese results suggested that OPN though PI3K/AKT/mammalian target of rapamycin signal pathway to up-regulate MMP-2 and VEGF expression, which contribute SGC-7901 cells to proliferation, invasion and migration. Thus, our results demonstrate that OPN may serve as a novel prognostic biomarkers as well as a potential therapeutic targets for GC.

Project description:BackgroundWith continuous advancement of industrial society, environmental pollution has become more and more serious. There has been an increase in infertility caused by environmental factors. Nonylphenol (NP) is a stable degradation product widely used in daily life and production and has been proven to affect male fertility. However, the underlying mechanisms therein are unclear. Thus, it is necessary to study the effect and mechanism of NP on spermatogonial stem cells (SSCs).AimTo investigate the cytotoxic effect of NP on SSCs via the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway.MethodsSSCs were treated with NP at 0, 10, 20 or 30 µmol. MTT assay was performed to evaluate the effect of NP on the proliferation of SSCs. Flow cytometry was conducted to measure SSC apoptosis. The expression of Bad, Bcl-2, cytochrome-c, pro-Caspase 9, SOX-2, OCT-4, Nanog, Nanos3, Stra8, Scp3, GFRα1, CD90, VASA, Nanos2, KIT, PLZF and PI3K/AKT/mTOR-related proteins was observed by western blot, and the mRNA expression of SOX-2, OCT-4 and Nanog was detected by quantitative reverse transcription polymerase chain reaction.ResultsCompared with untreated cells (0 μmol NP), SSCs treated with NP at all concentrations showed a decrease in cell proliferation and expression of Bcl-2, Nanog, OCT-4, SOX-2, Nanos3, Stra8, Scp3, GFRα1, CD90, VASA, Nanos2, KIT, and PLZF (P < 0.05), whereas the expression of Bad, cytochrome-c, and pro-Caspase 9 increased significantly (P < 0.05). We further examined the PI3K/AKT/mTOR pathway and found that the phosphorylation of PI3K, AKT, mTORC1, and S6K was significantly decreased by NP at all concentrations compared to that in untreated SSCs (P < 0.05). NP exerted the greatest effect at 30 μmol among all NP concentrations.ConclusionNP attenuated the proliferation, differentiation and stemness maintenance of SSCs while promoting apoptosis and oxidative stress. The associated mechanism may be related to the PI3K/AKT/mTOR pathway.

Dataset Information

Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by Membrane Targeting.

Publications

Regulation of the Target of Rapamycin and Other Phosphatidylinositol 3-Kinase-Related Kinases by Membrane Targeting.

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