Search results for "Mechanistic Target of Rapamycin Complex 1"
showing 10 items of 16 documents
Regulation of GSK-3 activity by curcumin, berberine and resveratrol: Potential effects on multiple diseases.
2017
Natural products or nutraceuticals promote anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway. This review will focus on the effects of curcumin (CUR), berberine (BBR) and resveratrol (RES), on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway, with a special focus on GSK-3. These natural products may regulate the pathway by multiple mechanisms including: reactive oxygen species (ROS), cytokine receptors, mirco-RNAs (miRs) and many others. CUR is present the root of turmeric (Curcuma longa). CUR is used in the treatment of many disorders, especially in those involving inflammatory p…
Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms
2018
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and…
Yeast thioredoxin reductase Trr1p controls TORC1-regulated processes
2018
The thioredoxin system plays a predominant role in the control of cellular redox status. Thioredoxin reductase fuels the system with reducing power in the form of NADPH. The TORC1 complex promotes growth and protein synthesis when nutrients, particularly amino acids, are abundant. It also represses catabolic processes, like autophagy, which are activated during starvation. We analyzed the impact of yeast cytosolic thioredoxin reductase TRR1 deletion under different environmental conditions. It shortens chronological life span and reduces growth in grape juice fermentation. TRR1 deletion has a global impact on metabolism during fermentation. As expected, it reduces oxidative stress tolerance…
TORC1 controls G1–S cell cycle transition in yeast via Mpk1 and the greatwall kinase pathway
2015
The target of rapamycin complex 1 (TORC1) pathway couples nutrient, energy and hormonal signals with eukaryotic cell growth and division. In yeast, TORC1 coordinates growth with G1–S cell cycle progression, also coined as START, by favouring the expression of G1 cyclins that activate cyclin-dependent protein kinases (CDKs) and by destabilizing the CDK inhibitor Sic1. Following TORC1 downregulation by rapamycin treatment or nutrient limitation, clearance of G1 cyclins and C-terminal phosphorylation of Sic1 by unknown protein kinases are both required for Sic1 to escape ubiquitin-dependent proteolysis prompted by its flagging via the SCFCdc4 (Skp1/Cul1/F-box protein) ubiquitin ligase complex.…
A genome-wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway
2019
Iron is an essential micronutrient that participates as a cofactor in a broad range of metabolic processes including mitochondrial respiration, DNA replication, protein translation and lipid biosynthesis. Adaptation to iron deficiency requires the global reorganization of cellular metabolism directed to optimize iron utilization. The budding yeast Saccharomyces cerevisiae has been widely used to characterize the responses of eukaryotic microorganisms to iron depletion. In this report, we used a genomic approach to investigate the contribution of transcription rates to the modulation of mRNA levels during adaptation of yeast cells to iron starvation. We reveal that a decrease in the activity…
mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity
2018
Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and lymphocyte proliferation. It is inhibited by the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2. Deletion of either gene results in robust activation of mTORC1. Mature B cells reside in the spleen at two major anatomical locations, the marginal zone (MZ) and follicles. The MZ constitutes the first line of humoral response against blood‐borne pathogens and undergoes atrophy in chronic inflammation. In previous work, we showed that mice deleted for TSC1 in their B cells (TSC1(BKO)) have almost no MZ B cells, whereas follicular B cells are minimally affected. To explore potential underl…
Muscle follistatin gene delivery increases muscle protein synthesis independent of periodical physical inactivity and fasting
2020
Blocking of myostatin and activins effectively counteracts muscle atrophy. However, the potential interaction with physical inactivity and fasting in the regulation of muscle protein synthesis is poorly understood. We used blockade of myostatin and activins by recombinant adeno-associated virus (rAAV)-mediated follistatin (FS288) overexpression in mouse tibialis anterior muscle. To investigate the effects on muscle protein synthesis, muscles were collected 7 days after rAAV-injection in the nighttime or in the daytime representing high and low levels of activity and feeding, respectively, or after overnight fasting, refeeding, or ad libitum feeding. Muscle protein synthesis was increased by…
The landscape of epilepsy-related GATOR1 variants
2019
Purpose:\ud \ud To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway.\ud \ud Methods:\ud \ud We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.\ud \ud Results:\ud \ud The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia…
Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins
2012
Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1–2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Bε protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, pr…
Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways
2020
Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types