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suppression of protein synthesis and induction of autophagy ..

KW - Protein synthesis

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Leucine and Protein Synthesis: mTOR and Beyond - …

mTOR (mammalian target of rapamycin) forms two distinct types of complex, mTORC (mTOR complex) 1 and 2. Rapamycin inhibits some of the functions of mTORC1, whereas newly developed mTOR kinase inhibitors interfere with the actions of both types of complex. We have explored the effects of rapamycin and mTOR kinase inhibitors on general protein synthesis and, using a new stable isotope-labelling method, the synthesis of specific proteins. In HeLa cells, rapamycin only had a modest effect on total protein synthesis, whereas mTOR kinase inhibitors decreased protein synthesis by approx. 30%. This does not seem to be due to the ability of mTOR kinase inhibitors to block the binding of eIFs (eukaryotic initiation factors) eIF4G and eIF4E. Analysis of the effects of the inhibitors on the synthesis of specific proteins showed a spectrum of behaviours. As expected, synthesis of proteins encoded by mRNAs that contain a 5'-TOP (5'-terminal oligopyrimidine tract) was impaired by rapamycin, but more strongly by mTOR kinase inhibition. Several proteins not known to be encoded by 5'-TOP mRNAs also showed similar behaviour. Synthesis of proteins encoded by 'non-TOP' mRNAs was less inhibited by mTOR kinase inhibitors and especially by rapamycin. The implications of our findings are discussed.

signalling and protein synthesis differed in ..

AB - FK506 and rapamycin are immunosuppressants that interfere with T cell activation. FK506 inhibits early events of T cell activation such as the induction of cytokine transcription, whereas rapamycin inhibits later interleukin 2 signalling events. However, both reagents either directly or indirectly reduce protein synthesis. Therefore a kinetic study was conducted in human primary T lymphocytes examining increased synthesis of proteins stimulated by either ionomycin + phorbol myristate acetate (PMA) or PMA alone. Three patterns of protein expression were observed. Synthesis of one group of proteins had enhanced synthesis with FK506, but reduced synthesis with rapamycin. A second group had reduced synthesis with rapamycin and either no change or a slight reduction with FK506 and a third group had reduction with both FK506 and rapamycin. One major protein of the first group, p42, had a rapid increase in synthesis that decreased by 8 h. Its synthesis was strongly enhanced by FK506, but reduced by rapamycin after ionomycin + PMA stimulation. In contrast, this protein was strongly induced by PMA alone in these cells and not affected by FK506 treatment, but still reduced by rapamycin. p42 was identified as cytoplasmic actin. mRNA levels of both γ- and β-actin were found to be enhanced with FK506 treatment suggesting that regulation of actin was at a transcriptional or post-transcriptional level. Results with actinomycin D indicated that FK506 is regulating actin biosynthesis at the post-transcriptional level. Rapamycin, however, appeared to be operating at the level of translation.

the Ang II–induced increase in protein synthesis

To determine whether rapamycin administration influences basal post-absorptive protein synthesis or breakdown in human skeletal muscle.

Short-term rapamycin administration may only impair protein synthesis in human skeletal muscle when combined with a stimulus such as resistance exercise or increased amino acid availability.

Finally, a number of studies have indicated that pharmacological inhibition of mTORC1 can provide neuroprotection in several in vivo models of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s and spinocerebellar ataxia type 3 (). Mounting evidence suggested that accumulation of misfolded and aggregated proteins is a common feature of these diseases, possibly caused by mTORC1-driven protein synthesis and defective autophagic degradation. Thus, suppression of protein synthesis and induction of autophagy by rapamycin may prevent or diminish protein aggregation. Moreover, a recent study has shown that rapamycin improves survival and attenuates disease progression in a mouse model (Ndufs4−/−) of Leigh syndrome, which is a neurological disorder characterized by a genetic defect that disrupts mitochondrial function (). For more detailed descriptions of the molecular mechanisms underlying how rapamycin exerts its neuroprotective effect, we refer the readers to a comprehensive review () ().

Rapamycin inhibits ribosomal protein synthesis and …

KW - Protein synthesis

In response to nutrients and growth factors, mTOR signaling serves as a key regulator of cell metabolism to coordinate the balance between anabolic and catabolic processes. When fasting, muscle and liver produce glucose via glycogenolysis (glycogen breakdown) and gluconeogenesis (glucose synthesis), and adipose tissue generates fatty acids through lipolysis, whereas, upon feeding, glycogenesis (glycogen synthesis) is favored in muscle and liver, and lipid uptake is favored in adipose tissue. Dysregulation of mTOR signaling has been linked to the development of a few metabolic diseases, such as diabetes and obesity (). Inhibition of the mTOR pathway by rapamycin has been demonstrated to have both beneficial and detrimental effects on metabolism. For example, acute rapamycin treatment improves insulin sensitivity in vitro and in vivo by disrupting a S6K-mediated feedback loop (described below) (; ). Moreover, rapamycin treatment inhibits human adipocyte differentiation in vitro () and protects against high fat diet-induced obesity in C57BL/6J mice (16 weeks) (). As discussed above, rapamycin appears capable of extending the lifespan of mice and preventing the onset of many age-related diseases, however, deleterious metabolic effects associated with rapamycin were also reported in other studies. For instance, Fradenkel et al found that rapamycin treatment (2 weeks) worsened hyperglycemia in a nutrition-dependent type 2 diabetes mouse model (). Similarly, the study by Chang et al demonstrated that rapamycin administration (6 weeks) exacerbates glucose intolerance in diet-induced obesity KK/HIJ mice (). Moreover, the study by Houde et al reported that rapamycin treatment (2 weeks) promoted insulin resistance and hyperlipidemia in rats (). It is currently unclear how rapamycin can have both positive and negative effects. In 2012, Lamming et al showed that rapamycin exerts different effects via separate mechanisms. They found that while reduced mTORC1 increases longevity and maintains normal glucose homeostasis, disruption of mTORC2 contributes to insulin resistance in vivo (). Additionally, Fang and colleagues suggested that these seemingly controversial findings might be explained by the duration of rapamycin treatment (). Their study compared various metabolic effects in male mice after 2, 6, or 20 weeks of rapamycin treatment. After 2 weeks of rapamycin treatment, the mice displayed smaller pancreas and enlarged liver. However, with prolonged treatment, these features returned to normal levels while adiposity, body weight (BW), and food consumption were significantly reduced. More strikingly, insulin sensitivity was altered with respect to different lengths of rapamycin treatment. Under normal physiological conditions, insulin suppresses hepatic gluconeogenesis while increasing lipogenesis, but in individuals with impaired insulin sensitivity, excess insulin is secreted to compensate for the insulin resistance. In agreement with previous findings by Houde et al (), insulin levels were increased after 2 weeks of rapamycin treatment, and the treated mice became glucose intolerant and insulin resistant. Interestingly, after 6 weeks of treatment the mice exhibited a transition to improved insulin sensitivity and by 20 weeks of rapamycin treatment, insulin levels were decreased while insulin sensitivity increased. Additional metabolic effects including lipid profile, oxygen consumption and ketogenesis were also altered in a manner relative to treatment durations (). Together, these remarkable findings may provide insight into how long-term treatment of rapamycin extends longevity in mice. However, how these studies will translate to human aging is unclear ().

To our knowledge, the mechanisms regulating human skeletal muscle protein metabolism in the basal state have yet to be the focus of any investigation. Thus, to provide a foundation from which to begin to examine these mechanisms, the purpose of this study was to determine whether rapamycin administration affects post-absorptive protein metabolism in human skeletal muscle. Specifically, we administered rapamycin under basal conditions and examined skeletal muscle protein synthesis rate, whole body protein breakdown, and downstream markers of mTORC1 signaling known to regulate both the synthesis (translation initiation) and breakdown (autophagy) of muscle proteins.

rapamycin on protein synthesis is ..
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  • both reagents either directly or indirectly reduce protein synthesis.

    Protein synthesis ..

  • Activated mTORC1 regulates protein synthesis by directly ..

    Branched-Chain Amino Acids Activate Key Enzymes in Protein Synthesis after Physical Exercise 1–3

  • effects on rates of protein synthesis.

    Immunosuppressants FK506 and rapamycin have different effects on the biosynthesis of ..

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BCAA supplementation can promote muscle protein synthesis and ..

N2 - FK506 and rapamycin are immunosuppressants that interfere with T cell activation. FK506 inhibits early events of T cell activation such as the induction of cytokine transcription, whereas rapamycin inhibits later interleukin 2 signalling events. However, both reagents either directly or indirectly reduce protein synthesis. Therefore a kinetic study was conducted in human primary T lymphocytes examining increased synthesis of proteins stimulated by either ionomycin + phorbol myristate acetate (PMA) or PMA alone. Three patterns of protein expression were observed. Synthesis of one group of proteins had enhanced synthesis with FK506, but reduced synthesis with rapamycin. A second group had reduced synthesis with rapamycin and either no change or a slight reduction with FK506 and a third group had reduction with both FK506 and rapamycin. One major protein of the first group, p42, had a rapid increase in synthesis that decreased by 8 h. Its synthesis was strongly enhanced by FK506, but reduced by rapamycin after ionomycin + PMA stimulation. In contrast, this protein was strongly induced by PMA alone in these cells and not affected by FK506 treatment, but still reduced by rapamycin. p42 was identified as cytoplasmic actin. mRNA levels of both γ- and β-actin were found to be enhanced with FK506 treatment suggesting that regulation of actin was at a transcriptional or post-transcriptional level. Results with actinomycin D indicated that FK506 is regulating actin biosynthesis at the post-transcriptional level. Rapamycin, however, appeared to be operating at the level of translation.

PI 3-kinase, mTOR, protein synthesis and cancer: …

The mammalian target of rapamycin (mTOR), which controls diverse cellular processes, is regulated by the integration of many signals. Rapamycin strongly inhibits the proliferation of many cancer cell lines and there is a high level of interest in its potential use as an anti-cancer agent. However, some tumours and cancer cells are resistant to rapamycin. This has prompted the development of mTOR kinase inhibitors (mTOR-KIs), such as PP242 and AZD8055, which compete with ATP for binding to the kinase domain in mTOR. In this research, I have studied whether the effects of mTOR-KIs on cell signalling and protein synthesis differed in comparison to those of rapamycin. My data shows that mTOR-KIs have strikingly different effects on proteins (including formation of the eIF4F translation factor complex) that control mRNA translation. Furthermore, while rapamycin only has a very small inhibitory effect on the rate of protein synthesis, mTOR-KIs have a much bigger effect. A new mass spectrometric approach, ?pSILAC‘, was applied to explore the effects of rapamycin and mTOR-KIs on the synthesis of specific proteins. The data from pSILAC reveal (i) mTOR-KIs impair synthesis of many proteins; (ii) rapamycin always inhibits less than mTOR-KIs; (iii) their effects are strongest for proteins encoded by 5‘-TOP mRNAs, but mTOR-KIs again inhibit more strongly; (iv) synthesis of some other proteins which are not encoded by known 5‘-TOP mRNAs shows a similar pattern of inhibition to 5‘-TOP mRNAs. These data show that pSILAC is a valuable tool for studying the control of the synthesis of specific proteins. I have also investigated the effects of disruption of eukaryotic translation initiation factor 4E (eIF4E) phosphorylation on (i) its modification by SUMO-1 (ii) TNF? biosynthesis in macrophages and (iii) the interaction with specific mRNAs encoding protumourigenic factors.

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