scholarly journals Sestrins at the Interface of ROS Control and Autophagy Regulation in Health and Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Marco Cordani ◽  
Miguel Sánchez-Álvarez ◽  
Raffaele Strippoli ◽  
Alexandr V. Bazhin ◽  
Massimo Donadelli
Keyword(s):  
Metabolic Disorders ◽  
Mammalian Target Of Rapamycin ◽  
Therapeutic Targets ◽  
Metabolic Stress ◽  
Dependent Protein Kinase ◽  
Energy Sensor ◽  
Positive Regulators ◽  
Dependent Protein ◽  
Health And Disease ◽  
Broad Interest

Reactive oxygen species (ROS) and autophagy are two highly complex and interrelated components of cell physiopathology, but our understanding of their integration and their contribution to cell homeostasis and disease is still limited. Sestrins (SESNs) belong to a family of highly conserved stress-inducible proteins that orchestrate antioxidant and autophagy-regulating functions protecting cells from various noxious stimuli, including DNA damage, oxidative stress, hypoxia, and metabolic stress. They are also relevant modulators of metabolism as positive regulators of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibitors of mammalian target of rapamycin complex 1 (mTORC1). Since perturbations in these pathways are central to multiple disorders, SESNs might constitute potential novel therapeutic targets of broad interest. In this review, we discuss the current understanding of regulatory and effector networks of SESNs, highlighting their significance as potential biomarkers and therapeutic targets for different diseases, such as aging-related diseases, metabolic disorders, neurodegenerative diseases, and cancer.

scholarly journals The functions and roles of sestrins in regulating human diseases

2022 ◽  
Vol 27 (1) ◽  
Author(s):  
Yitong Chen ◽  
Tingben Huang ◽  
Zhou Yu ◽  
Qiong Yu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Musculoskeletal System ◽  
Therapeutic Process ◽  
Mammalian Target Of Rapamycin ◽  
Human Diseases ◽  
Dependent Protein Kinase ◽  
The Past ◽  
Apoptosis Inhibition ◽  
Energy Sensor ◽  
Dependent Protein ◽  
New Evidence

AbstractSestrins (Sesns), highly conserved stress-inducible metabolic proteins, are known to protect organisms against various noxious stimuli including DNA damage, oxidative stress, starvation, endoplasmic reticulum (ER) stress, and hypoxia. Sesns regulate metabolism mainly through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Sesns also play pivotal roles in autophagy activation and apoptosis inhibition in normal cells, while conversely promoting apoptosis in cancer cells. The functions of Sesns in diseases such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and cancer have been broadly investigated in the past decades. However, there is a limited number of reviews that have summarized the functions of Sesns in the pathophysiological processes of human diseases, especially musculoskeletal system diseases. One aim of this review is to discuss the biological functions of Sesns in the pathophysiological process and phenotype of diseases. More significantly, we include some new evidence about the musculoskeletal system. Another purpose is to explore whether Sesns could be potential biomarkers or targets in the future diagnostic and therapeutic process.

scholarly journals microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle

2018 ◽  
Vol 115 (46) ◽  
pp. E10849-E10858 ◽  
Author(s):  
Yan Li ◽  
Jingjing Jiang ◽  
Wei Liu ◽  
Hui Wang ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Death ◽  
Cell Fate ◽  
Metabolic Regulation ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Stress ◽  
Muscle Weight ◽  
Dependent Protein ◽  
Metabolic Checkpoints

The metabolic regulation of cell death is sophisticated. A growing body of evidence suggests the existence of multiple metabolic checkpoints that dictate cell fate in response to metabolic fluctuations. However, whether microRNAs (miRNAs) are able to respond to metabolic stress, reset the threshold of cell death, and attempt to reestablish homeostasis is largely unknown. Here, we show that miR-378/378* KO mice cannot maintain normal muscle weight and have poor running performance, which is accompanied by impaired autophagy, accumulation of abnormal mitochondria, and excessive apoptosis in skeletal muscle, whereas miR-378 overexpression is able to enhance autophagy and repress apoptosis in skeletal muscle of mice. Our in vitro data show that metabolic stress-responsive miR-378 promotes autophagy and inhibits apoptosis in a cell-autonomous manner. Mechanistically, miR-378 promotes autophagy initiation through the mammalian target of rapamycin (mTOR)/unc-51-like autophagy activating kinase 1 (ULK1) pathway and sustains autophagy via Forkhead box class O (FoxO)-mediated transcriptional reinforcement by targeting phosphoinositide-dependent protein kinase 1 (PDK1). Meanwhile, miR-378 suppresses intrinsic apoptosis initiation directly through targeting an initiator caspase—Caspase 9. Thus, we propose that miR-378 is a critical component of metabolic checkpoints, which integrates metabolic information into an adaptive response to reduce the propensity of myocytes to undergo apoptosis by enhancing the autophagic process and blocking apoptotic initiation. Lastly, our data suggest that inflammation-induced down-regulation of miR-378 might contribute to the pathogenesis of muscle dystrophy.

AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer

2011 ◽  
Vol 39 (1) ◽  
pp. 1-13 ◽  
Author(s):  
D. Grahame Hardie
Keyword(s):  
Protein Kinase ◽  
Metabolic Disorders ◽  
Adenine Nucleotides ◽  
Metabolic Stress ◽  
Branch Points ◽  
Atp Production ◽  
Nucleotide Binding Sites ◽  
Anticancer Effects ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

It is essential to life that a balance is maintained between processes that produce ATP and those that consume it. An obvious way to do this would be to have systems that monitor the levels of ATP and ADP, although because of the adenylate kinase reaction (2ADP↔ATP+AMP), AMP is actually a more sensitive indicator of energy stress than ADP. Following the discoveries that glycogen phosphorylase and phosphofructokinase were regulated by AMP and ATP, Daniel Atkinson proposed that all enzymes at branch points between biosynthesis and degradation would be regulated by adenine nucleotides. This turned out to be correct, but what Atkinson did not anticipate was that sensing of nucleotides would, in most cases, be performed not by the metabolic enzymes themselves, but by a signalling protein, AMPK (AMP-activated protein kinase). AMPK occurs in essentially all eukaryotes and consists of heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits, of which the latter carries the nucleotide-binding sites. Once activated by a metabolic stress, it phosphorylates numerous targets that alter enzyme activity and gene expression to initiate corrective responses. In lower eukaryotes, it is critically involved in the responses to starvation for a carbon source. Because of its ability to switch cellular metabolism from anabolic to catabolic mode, AMPK has become a key drug target to combat metabolic disorders associated with overnutrition such as Type 2 diabetes, and some existing anti-diabetic drugs (e.g. metformin) and many ‘nutraceuticals’ work by activating AMPK, usually via inhibition of mitochondrial ATP production. AMPK activators also potentially have anticancer effects, and there is already evidence that metformin provides protection against the initiation of cancer. Whether AMPK activators can be used to treat existing cancer is less clear, because many tumour cells appear to have been selected for mutations that inactivate the AMPK system. However, if we can identify the various mechanisms by which this occurs, we may be able to find ways of overcoming it.

Activation of the cardiac mTOR/p70S6K pathway by leucine requires PDK1 and correlates with PRAS40 phosphorylation

2010 ◽  
Vol 298 (4) ◽  
pp. E761-E769 ◽  
Author(s):  
Cossette Sanchez Canedo ◽  
Bénédicte Demeulder ◽  
Audrey Ginion ◽  
Jose R. Bayascas ◽  
Jean-Luc Balligand ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mammalian Target Of Rapamycin ◽  
Phosphorylation Site ◽  
Phosphatidylinositol 3 Kinase ◽  
Dependent Protein Kinase ◽  
S6 Kinase ◽  
Mtor Phosphorylation ◽  
Dependent Protein ◽  
Ribosomal S6 Kinase ◽  
Mtor Activity

Like insulin, leucine stimulates the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) axis in various organs. Insulin proceeds via the canonical association of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent protein kinase-1 (PDK1), and protein kinase B (PKB/Akt). The signaling involved in leucine effect, although known to implicate a PI3K mechanism independent of PKB/Akt, is more poorly understood. In this study, we investigated whether PDK1 could also participate in the events leading to mTOR/p70S6K activation in response to leucine in the heart. In wild-type hearts, both leucine and insulin increased p70S6K activity whereas, in contrast to insulin, leucine was unable to activate PKB/Akt. The changes in p70S6K activity induced by insulin and leucine correlated with changes in phosphorylation of Thr389, the mTOR phosphorylation site on p70S6K, and of Ser2448 on mTOR, both related to mTOR activity. Leucine also triggered phosphorylation of the proline-rich Akt/PKB substrate of 40 kDa (PRAS40), a new pivotal mTOR regulator. In PDK1 knockout hearts, leucine, similarly to insulin, failed to induce the phosphorylation of mTOR and p70S6K, leading to the absence of p70S6K activation. The loss of leucine effect in absence of PDK1 correlated with the lack of PRAS40 phosphorylation. Moreover, the introduction in PDK1 of the L155E mutation, which is known to preserve the insulin-induced and PKB/Akt-dependent phosphorylation of mTOR/p70S6K, suppressed all leucine effects, including phosphorylation of mTOR, PRAS40, and p70S6K. We conclude that the leucine-induced stimulation of the cardiac PRAS40/mTOR/p70S6K pathway requires PDK1 in a way that differs from that of insulin.

Abstract 11919: AMP-Activated Protein Kinase Response to Metabolic Stress: A Novel Determinant of Atrial Fibrillation Progression

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Masahide Harada ◽  
Xiao- Y Qi ◽  
Artak Tadevosyan ◽  
Niels Voigt ◽  
Matthias Karck ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Protein Kinase ◽  
Left Atrial ◽  
Metabolic Stress ◽  
Ampk Activation ◽  
Dependent Protein Kinase ◽  
Α Subunit ◽  
Dependent Protein ◽  
Novel Target ◽  
Amp Activated Protein Kinase

Introduction: Metabolic stress is observed in clinical and experimental atrial fibrillation (AF). Metabolic stress activates AMP-dependent protein kinase (AMPK) via phosphorylation; activated AMPK produces compensatory changes in the determinants of energy balance. Here, we examined AMPK responses in AF and their role in remodeling responses of atrial Ca 2+ handling and contractility. Methods: AMPK and Cav1.2 protein were quantified by immunoblot. Ca 2+ transients (CaTs, Indo1 AM), cell shortening (CS, videometry), L-type Ca 2+ ( I Ca,L ) and NCX ( I NCX ) current (patch clamp) were measured in dog left atrial (LA) cardiomyocytes (CMs) under metabolic stress due to glycolysis inhibition (GI, 10 mM 2-deoxyglucose/10 mM pyruvate). Results: In dogs with 1-wk electrically-maintained AF (n=4), the phosphorylation ratio (PhR) of AMPK (indicating activation) increased in LA by 101%* (*p<0.05) vs. controls (n=4). Metabolic stress due to GI in 2 Hz paced LA CMs increased AMPK PhR by 103%* vs. quiescent CMs. In 2 Hz paced cells, the AMPK inhibitor CompC (10 μM) decreased LA CaT and CS by 58%* and 51%* vs. control, but the AMPK activator AICAR (1 mM) restored CaT and CS by 75%* and 53%* vs. CompC alone, supporting AMPK-dependent regulation. CompC decreased I Ca,L and I Ca,L -triggered CaT by 46%* and 37%*. AMPKα protein coimmunoprecipitated with Ca v 1.2 protein, suggesting that AMPK is physically coupled with the I Ca,L channel α-subunit. CompC also decreased SR Ca 2+ content by 53%* vs. control ( I NCX simultaneously measured with caffeine-induced CaT). AMPK PhR was greater by 61%* in paroxysmal AF (pAF, n=7) patient atria vs. sinus rhythm controls (n=10), whereas AMPK PhR was decreased in chronic AF (cAF) patients (n=9) by 27%*, suggesting that the level of AMPK activation may govern the chronicization of AF. Conclusions: AF activates AMPK. Under AF-induced metabolic stress, AMPK activation limits AF-promoting abnormalities in LA I Ca,L , Ca 2+ handling and contractility. pAF patients have AMPK activation, protecting them against chronicization, whereas cAF patients have reduced AMPK activation. Thus, the response of AMPK to AF-related metabolic stress might be a crucial determinant of AF chronicization, and AMPK-manipulation may be a novel target to prevent AF progression.

scholarly journals cGMP-Dependent Protein Kinase Inhibitors in Health and Disease

2013 ◽  
Vol 6 (2) ◽  
pp. 269-286 ◽  
Author(s):  
Stefanie Wolfertstetter ◽  
Johannes Huettner ◽  
Jens Schlossmann
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Health And Disease

Blebbistatin induces chondrogenesis of single mesenchymal cells via PI3K/PDK1/mTOR/p70S6K pathway

Biologia ◽  
2017 ◽  
Vol 72 (6) ◽  
Author(s):  
Hyoin Kim ◽  
Dong Hyun Kim ◽  
Bohyeon Jeong ◽  
Ju-Hee Kim ◽  
Sun-Ryung Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mesenchymal Cells ◽  
Akt Inhibitor ◽  
Dependent Protein Kinase ◽  
Ribosomal Protein S6 ◽  
Monolayer Cultures ◽  
Pi3k Inhibition ◽  
Dependent Protein ◽  
Phosphoinositide 3 Kinase ◽  
Mtor Complex 1

AbstractRearrangement of the actin cytoskeleton plays an inductive role in chondrogenic differentiation. Our previous study showed that blebbistatin, an inhibitor of myosin II, removes actin stress fibres and induces chondrogenesis of mesenchymal cells in monolayer cultures. In the present study, we investigated signalling pathways implicated in the induction of chondrogenesis by dissolving actin stress fibres after blebbistatin treatment. Blebbistatin increased the activity of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K with LY294002 blocked blebbistatin-induced chondrogenesis without affecting blebbistatin-induced reorganization of actin filaments. Blebbistatin also upregulated the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), and inhibition of PDK1 with GSK2334470 suppressed blebbistatin-induced chondrogenesis, indicating that removal of actin stress fibres by blebbistatin induced chondrogenesis by activating PI3K/PDK1. Although inhibition of Akt activity by Akt inhibitor IV blocked blebbistatin-induced chondrogenesis, phosphorylation of Akt was not affected by blebbistatin. Blebbistatin increased the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and p70 ribosomal protein S6 kinase (p70S6K). Inhibition of mTOR with rapamycin almost completely abolished the phosphorylation of p70S6K. Inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) with pp242 diminished phosphorylation of Akt at Ser473, whereas inhibition of mTORC1 with rapamycin did not. However, blebbistatin did not affect the phosphorylation of mTOR at Ser2481. Taken together, the present results suggest that blebbistatin induces chondrogenesis by activating the PI3K/PDK1/mTOR/p70S6K pathway. Our data also indicate that Akt activity is essential for chondrogenesis but is regulated by mTORC2, which is independent of blebbistatin treatment.

scholarly journals CTNI-11. CC-115 IN NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II RANDOMIZED BAYESIAN ADAPTIVE PLATFORM TRIAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii43-ii44
Author(s):  
Rifaquat Rahman ◽  
Lorenzo Trippa ◽  
Geoffrey Fell ◽  
Eudocia Lee ◽  
Isabel Arrillaga-Romany ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Dependent Protein Kinase ◽  
Free Survival ◽  
Significant Difference ◽  
Newly Diagnosed Glioblastoma ◽  
Dependent Protein ◽  
Human Use ◽  
Screening Trial

Abstract BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade &gt; 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to &lt; 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

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