The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth

Gonzalez, Suam; Rallis, Charalampos

doi:10.3389/fcell.2017.00061

Cited by 55 publications

(45 citation statements)

References 84 publications

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“…). mTORC2, that contains the catalytic regulator Rictor, has opposing functions compared to mTORC1 (Gonzalez and Rallis ) and it has turned out that mTORC2‐mediated phosphorylation and activation of Akt seem to be required for cell cycle progression in cancer cells (Hietakangas and Cohen ). We have previously shown that mTORC1 activity, detected as phosphorylation of 4E‐BP1, is transiently increased in mouse fibroblasts following hypoosmotic exposure, that is, mTOR activity is significantly increased and boosted by PTEN inhibition within minutes following osmotic cell swelling but reduced following prolonged (4 h/24 h) hypotonic adaptation (Lambert et al.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced modulation of volume-regulated anions channels in human alveolar carcinoma cells

2018

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Shift in the cellular homeostasis of the organic osmolyte taurine has been associated with dysregulation of the volume‐regulated anion channel (VRAC) complex, which comprises leucine‐rich repeat‐containing family 8 members (LRRC8A‐E). Using SDS‐PAGE, western blotting, qRT‐PCR, and tracer technique ([3H]taurine) we demonstrate that reactive oxygen species (ROS) and the cell growth‐associated kinases Akt/mTOR, play a role in the regulation of VRAC in human alveolar cancer (A549) cells. LRRC8A is indispensable for VRAC activity and long‐term exposure to hypoosmotic challenges and/or ROS impairs VRAC activity, not through reduction in total LRRC8A expression or LRRC8A availability in the plasma membrane, but through oxidation/inactivation of kinases/phosphatases that control VRAC activity once it has been instigated. Pursuing Akt signaling via the serine/threonine kinase mTOR, using mTORC1 inhibition (rapamycin) and mTORC2 obstruction (Rictor knockdown), we demonstrate that interference with the PI3K‐mTORC2‐Akt signaling‐axes obstructs stress‐induced taurine release. Furthermore, we show that an increased LRRC8A expression, following exposure to cisplatin, ROS, phosphatase/lipoxygenase inhibitors, and antagonist of CysLT1‐receptors, correlates an increased activation of the proapoptotic transcription factor p53. It is suggested that an increase in LRRC8A protein expression could be taken as an indicator for cell stress and limitation in VRAC activity.

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Section: Discussionmentioning

confidence: 99%

Stress-induced modulation of volume-regulated anions channels in human alveolar carcinoma cells

2018

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“…The conserved Target of Rapamycin (TOR) signaling pathway is a key regulator for cellular growth and metabolism in response to nutrients and energy (Gonzalez and Rallis, 2017;González and Hall, 2017;Valvezan and Manning, 2019;Wei et al, 2013). In most organisms, TOR functions via two distinct multi-protein complexes, TORC1 and TORC2, which coordinate various aspects of growth and associated cellular processes (Hartmuth and Petersen, 2009;Ikai et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In all organisms tested, TORC1 signaling promotes ageing and shortens lifespan (Gonzalez and Rallis, 2017;González and Hall, 2017;Kaeberlein, 2010;Wei et al, 2013). Lifespan is influenced by multiple TORC1-dependent processes, including mitochondrial activity (Hill and Van Remmen, 2014), autophagy (Saxton and Sabatini, 2017), and protein translation (Bjedov and Partridge, 2011;.…”

Section: Introductionmentioning

confidence: 99%

The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1

Rodríguez-López

Gonzalez

Hillson

et al. 2019

Preprint

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Target of Rapamycin Complex 1 (TORC1) signaling promotes growth and ageing. Inhibition of TORC1 leads to a down-regulation of factors that stimulate protein translation, including RNA polymerase III, which in turn contributes to longevity. TORC1-mediated posttranscriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less well understood. Here we screened fission yeast deletion mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Mutants lacking the GATA transcription factor Gaf1 (gaf1Δ) grew normally even in high doses of Torin1. The gaf1Δ mutants shortened the chronological lifespan of non-dividing cells and diminished the lifespan extension triggered by Torin1 treatment. Expression profiling and genome-wide binding experiments showed that, after TORC1 inhibition, Gaf1 directly up-regulated genes for small-molecule metabolic pathways and indirectly repressed genes for protein translation.Surprisingly, Gaf1 also bound to the tRNA genes and down-regulated them, so functions as a transcription factor for genes transcribed by RNA polymerase III. We conclude that Gaf1 controls the transcription of both coding and tRNA genes to inhibit translation and growth downstream of TORC1.

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“…Cells live in dynamic environments to which they must adapt [1,2,3]. In both physiological and pathological conditions, cells can respond to cytokines and other types of signals by changing their sizes [4,5,6,7].…”

Section: Introductionmentioning

confidence: 99%

Electromechanics and Volume Dynamics in Non-excitable Tissue Cells

Yellin

Sreenivasan³

et al. 2018

Preprint

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Cell volume regulation is fundamentally important in phenomena such as cell growth, proliferation, tissue homeostasis and embryogenesis. How the cell size is set, maintained, and changed over a cell's lifetime is not well understood. In this work we focus on how the volume of non-excitable tissue cells is coupled to the cell membrane electrical potential and the concentration of membrane-permeable ions in the cell environment. Specifically, we demonstrate that a sudden cell depolarization using the whole cell patch clamp results in a 30 percent increase in cell volume, while hyperpolarization results in a slight volume decrease. We find that cell volume can be partially controlled by changing the chloride or the sodium/potassium concentrations in the extracellular environment while maintaining a constant external osmotic pressure. Depletion of external chloride leads to a volume decrease in suspended HN31 cells.Introducing cells to a high potassium solution causes volume increase by up to 50%. Cell volume is also influenced by cortical tension: actin depolymerization leads to cell volume increase. We present an electrophysiology model of water dynamics driven by changes in membrane potential and in the concentration of permeable ions in the cell surrounding. The model quantitatively predicts that the cell volume is determined by the total amount of intracellular ion and protein content.

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The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth

Cited by 55 publications

References 84 publications

Stress-induced modulation of volume-regulated anions channels in human alveolar carcinoma cells

Stress-induced modulation of volume-regulated anions channels in human alveolar carcinoma cells

The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1

Electromechanics and Volume Dynamics in Non-excitable Tissue Cells

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