The expanding TOR signaling network

Martin, Dietmar E.; Hall, Michael N.

doi:10.1016/j.ceb.2005.02.008

Cited by 488 publications

(383 citation statements)

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“…Attenuation of TOR function in yeast, worms and flies results in a significant increase of lifespan (Kaeberlein et al, 2005;Kapahi et al, 2004;Martin and Hall, 2005;Vellai et al, 2003). TOR signalling controls various growth-related processes, including protein synthesis and autophagy, both of which are implicated in the modulation of lifespan.…”

Section: Tor Signallingmentioning

confidence: 99%

Autophagy and ageing: Insights from invertebrate model organisms

Lionaki

Markaki

Tavernarakis

2013

Ageing Research Reviews

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a b s t r a c tAgeing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.

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Section: Tor Signallingmentioning

confidence: 99%

Autophagy and ageing: Insights from invertebrate model organisms

Lionaki

Markaki

Tavernarakis

2013

Ageing Research Reviews

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“…Rapamycin is an antibiotic immunosuppressant compound known to directly antagonize the mammalian target of rapamycin (mTOR) cascade which lies downstream of the insulin like growth factor cascade and leads to activation of several downstream kinase proteins including p70S6 kinase that phosphorylate proteins known to regulate cell growth (Schmelzle and Hall, 2000, Potter et al, 2001, Hay and Sonenberg, 2004Soliman, 2005;Martin and Hall, 2005). Recent evidence suggests that loss of function mutations in the tuberous sclerosis complex genes (TSC1 and TSC2) leads to constitutive activation of the mTOR cascade (Arrazola et al, 2002;Inoki et al, 2002;Kenerson et al, 2002;Onda et al, 2002, Tee et al, 2002, El-Hashemite et al, 2003 and disturbs the regulation of neuronal morphology and function mediated by TSC1 and TSC2 (Tavazoie et al, 2005) resulting in abnormal neuronal organization and seizures (Uhlmann et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

et al. 2007

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SummaryPurpose-We assayed the effects of rapamycin, an immunomodulatory agent known to inhibit the activity of the mammalian target of rapamycin (mTOR) cascade, on candidate gene expression and single unit firing properties in cultured rat hippocampal neurons as a strategy to define the effects of rapamycin on neuronal gene transcription and excitability.Methods-Rapamycin was added (100 nM) to cultured hippocampal neurons on days 3 and 14. Neuronal somatic size and dendritic length were assayed by immunohistochemistry and digital imaging. Radiolabeled mRNA was amplified from single hippocampal pyramidal neurons and used to probe cDNA arrays containing over 100 distinct candidate genes including cytoskeletal element, growth factor, transcription factor, neurotransmitter, and ion channel genes. In addition, the effects of rapamycin (200 nM) on spontaneous neuronal activity and voltage-dependent currents was assessed.Results-There were no effects of rapamycin on cell size or dendrite length. Rapamycin altered expression of distinct mRNAs in each gene family on days 3 and 14 in culture. Single unit recordings from neurons exposed to rapamycin exhibited no change from baseline. When spontaneous activity was increased by blocking GABA-mediated inhibition with bicuculline, a fraction of the neurons exhibited a decreased duration of spontaneous bursts and a decrease in synaptic inputs. Rapamycin did not appear to alter voltage dependent Na+ or K+ currents underlying action potentials.Conclusions-These data demonstrate that rapamycin does not produce neurotoxicity nor alter dendritic growth and complexity in vitro and does not significantly alter voltage gated sodium and potassium currents. Rapamycin does affect neuronal gene transcription in vitro. Use of rapamycin in clinical trials for patients with tuberous sclerosis complex should involve vigilance for possible effects on seizure frequency and neurocognitive function.

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“…4 mTOR kinase is the key enzyme in the signaling pathway and is activated by Rheb GTPase. 2,[6][7][8][9][10][11][12][13][14][15] mTOR exists in two complexes, mTORC1 and mTORC2. In mTORC1, mTOR is complexed with Raptor and G b L and phosphorylates S6K and 4E-BP1.…”

Section: Introductionmentioning

confidence: 99%