scholarly journals Mitochondrial localization of SESN2

2019 ◽  
Author(s):  
Irina E. Kovaleva ◽  
Artem V. Tokarchuk ◽  
Andrei O. Zeltukhin ◽  
Grigoriy Safronov ◽  
Aleksandra G. Evstafieva ◽  
...  
Keyword(s):  
Protein Complex ◽  
Inhibitory Effect ◽  
Small Gtpase ◽  
Stress Factors ◽  
Mitochondrial Localization ◽  
Mitochondrial Functions ◽  
Ros Accumulation ◽  
Evolutionarily Conserved ◽  
Established Role

SESN2 is a member of evolutionarily conserved sestrin protein family found in most of Metazoa species. SESN2 is transcriptionally activated by many stress factors including metabolic derangements, oxidants and DNA-damage. As a result, SESN2 controls ROS accumulation, metabolism and cell viability. The best known function of SESN2 is the regulation of mechanistic target of rapamycin complex 1 kinase (mTORC1) that plays the central role in the stimulation of cell growth and suppression of autophagy. SESN2 inhibits mTORC1 activity through interaction with the GATOR2 protein complex that suppresses an inhibitory effect of GATOR2 on the GATOR1 protein complex. GATOR1 inhibits mTORC1 through its GAP activity toward the small GTPase RagA/B which in complex with RagC/D proteins stimulate mTORC1 translocation to the lysosomes where this kinase is activated by small GTPase Rheb. Despite the well-established role of SESN2 in mTORC1 inhibition, the other SESN2 activities are not well characterised. We recently showed that SESN2 can control mitochondrial function and cell death via mTORC1-independent mechanisms and these activities might be explained by direct effects of SESN2 on mitochondria. In this work we examined mitochondrial localization of SESN2 and demonstrated that SESN2 is located on mitochondria and can be directly involved in the regulation of mitochondrial functions.

Myotubularins, PtdIns5P, and ROS in ABA-mediated stomatal movements in dehydrated Arabidopsis seedlings

2018 ◽  
Vol 45 (2) ◽  
pp. 259 ◽  
Author(s):  
Akanksha Nagpal ◽  
Ammar Hassan ◽  
Ivan Ndamukong ◽  
Zoya Avramova ◽  
František Baluška
Keyword(s):  
Cell Signalling ◽  
Membrane Dynamics ◽  
Dehydration Stress ◽  
Oxygen Species ◽  
Secondary Messenger ◽  
Signalling Molecule ◽  
Ros Accumulation ◽  
Evolutionarily Conserved ◽  
Stomatal Movements

Myotubularins (MTMs) are lipid phosphoinositide 3-phosphate phosphatases and the product of their enzyme activity – phosphoinositide 5-phosphate (PtdIns5P) – functions as a signalling molecule in pathways involved in membrane dynamics and cell signalling. Two Arabidopsis genes, AtMTM1 and AtMTM2, encode enzymatically active phosphatases but although AtMTM1 deficiency results in increased tolerance to dehydration stress and a decrease in cellular PtdIns5P, the role of AtMTM2 is less clear, as it does not contribute to the PtdIns5P pool upon dehydration stress. Here we analysed the involvement of AtMTM1, AtMTM2 and PtdIns5P in the response of Arabidopsis seedlings to dehydration stress/ABA, and found that both AtMTM1 and AtMTM2 were involved but affected oppositely stomata movement and the accumulation of reactive oxygen species (ROS, e.g. H2O2). Acting as a secondary messenger in the ABA-induced ROS production in guard cells, PtdIns5P emerges as an evolutionarily conserved signalling molecule that calibrates cellular ROS under stress. We propose the biological relevance of the counteracting AtMTM1 and AtMTM2 activities is to balance the ABA-induced ROS accumulation and cellular homeostasis under dehydration stress.

scholarly journals The RNA helicase DDX3 induces neural crest by promoting AKT activity

Development ◽  
2020 ◽  
pp. dev.184341
Author(s):  
Mark Perfetto ◽  
Xiaolu Xu ◽  
Congyu Lu ◽  
Yu Shi ◽  
Natasha Yousaf ◽  
...  
Keyword(s):  
Neural Crest ◽  
Birth Defects ◽  
Kinase Activity ◽  
Rna Helicase ◽  
Small Gtpase ◽  
Potential Mechanism ◽  
Downstream Signaling ◽  
Downstream Effectors ◽  
Evolutionarily Conserved

Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many patients carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3β, leading to reduced levels of β-catenin and Snai1, two GSK3β substrates that are critical for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by patients harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

scholarly journals The RNA helicase DDX3 induces neural crest by promoting AKT activity

2019 ◽  
Author(s):  
Mark Perfetto ◽  
Xiaolu Xu ◽  
Natasha Yousaf ◽  
Jiejing Li ◽  
Shuo Wei
Keyword(s):  
Neural Crest ◽  
Birth Defects ◽  
Kinase Activity ◽  
Rna Helicase ◽  
Small Gtpase ◽  
Potential Mechanism ◽  
Downstream Signaling ◽  
Downstream Effectors ◽  
Evolutionarily Conserved

AbstractMutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many patients carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3β, leading to reduced levels of β-catenin and Snai1, two GSK3β substrates that are critical for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by patients harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

scholarly journals A novel physiological role for ARF1 in the formation of bidirectional tubules from the Golgi

2017 ◽  
Vol 28 (12) ◽  
pp. 1676-1687 ◽  
Author(s):  
Francesca Bottanelli ◽  
Nicole Kilian ◽  
Andreas M. Ernst ◽  
Felix Rivera-Molina ◽  
Lena K. Schroeder ◽  
...  
Keyword(s):  
Physiological Role ◽  
Super Resolution ◽  
Close Packing ◽  
Small Gtpase ◽  
Stimulated Emission ◽  
Mutant Form ◽  
Coat Proteins ◽  
Gtp Hydrolysis ◽  
Established Role

Capitalizing on CRISPR/Cas9 gene-editing techniques and super-resolution nanoscopy, we explore the role of the small GTPase ARF1 in mediating transport steps at the Golgi. Besides its well-established role in generating COPI vesicles, we find that ARF1 is also involved in the formation of long (∼3 µm), thin (∼110 nm diameter) tubular carriers. The anterograde and retrograde tubular carriers are both largely free of the classical Golgi coat proteins coatomer (COPI) and clathrin. Instead, they contain ARF1 along their entire length at a density estimated to be in the range of close packing. Experiments using a mutant form of ARF1 affecting GTP hydrolysis suggest that ARF1[GTP] is functionally required for the tubules to form. Dynamic confocal and stimulated emission depletion imaging shows that ARF1-rich tubular compartments fall into two distinct classes containing 1) anterograde cargoes and clathrin clusters or 2) retrograde cargoes and coatomer clusters.

Ypt1 and COPII vesicles act in autophagosome biogenesis and the early secretory pathway

2015 ◽  
Vol 43 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Saralin Davis ◽  
Susan Ferro-Novick
Keyword(s):  
Coat Protein ◽  
Protein Complex ◽  
Intracellular Trafficking ◽  
Secretory Pathway ◽  
Cell Stress ◽  
Complex Ii ◽  
Early Secretory Pathway ◽  
Copii Vesicles ◽  
Established Role

The GTPase Ypt1, Rab1 in mammals functions on multiple intracellular trafficking pathways. Ypt1 has an established role on the early secretory pathway in targeting coat protein complex II (COPII) coated vesicles to the cis-Golgi. Additionally, Ypt1 functions during the initial stages of macroautophagy, a process of cellular degradation induced during periods of cell stress. In the present study, we discuss the role of Ypt1 and other secretory machinery during macroautophagy, highlighting commonalities between these two pathways.

scholarly journals Methylation of histone H3K23 blocks DNA damage in pericentric heterochromatin during meiosis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Romeo Papazyan ◽  
Ekaterina Voronina ◽  
Jessica R Chapman ◽  
Teresa R Luperchio ◽  
Tonya M Gilbert ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Model Organism ◽  
Pericentric Heterochromatin ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Established Role

Despite the well-established role of heterochromatin in protecting chromosomal integrity during meiosis and mitosis, the contribution and extent of heterochromatic histone posttranslational modifications (PTMs) remain poorly defined. Here, we gained novel functional insight about heterochromatic PTMs by analyzing histone H3 purified from the heterochromatic germline micronucleus of the model organism Tetrahymena thermophila. Mass spectrometric sequencing of micronuclear H3 identified H3K23 trimethylation (H3K23me3), a previously uncharacterized PTM. H3K23me3 became particularly enriched during meiotic leptotene and zygotene in germline chromatin of Tetrahymena and C. elegans. Loss of H3K23me3 in Tetrahymena through deletion of the methyltransferase Ezl3p caused mislocalization of meiosis-induced DNA double-strand breaks (DSBs) to heterochromatin, and a decrease in progeny viability. These results show that an evolutionarily conserved developmental pathway regulates H3K23me3 during meiosis, and our studies in Tetrahymena suggest this pathway may function to protect heterochromatin from DSBs.

The uncoupling of respiration in plant mitochondria: keeping reactive oxygen and nitrogen species under control

2020 ◽  
Author(s):  
Vasily N Popov ◽  
Mikhail Y Syromyatnikov ◽  
Alisdair R Fernie ◽  
Subhra Chakraborty ◽  
Kapuganti Jagadis Gupta ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Uncoupling Protein ◽  
Plant Mitochondria ◽  
Reactive Oxygen ◽  
Stress Factors ◽  
Atp Production ◽  
Alternative Pathways ◽  
Mitochondrial Functions ◽  
Far From Equilibrium

Abstract Plant mitochondrial respiration involves the operation of various alternative pathways. These pathways participate, both directly and indirectly, in the maintenance of mitochondrial functions though they do not contribute to energy production, being uncoupled from the generation of an electrochemical gradient across the mitochondrial membrane and thus from ATP production. Recent findings suggest that uncoupled respiration is involved in reactive oxygen species (ROS) and nitric oxide (NO) scavenging, regulation, and homeostasis. Here we discuss specific roles and possible functions of uncoupled mitochondrial respiration in ROS and NO metabolism. The mechanisms of expression and regulation of the NDA-, NDB- and NDC-type non-coupled NADH and NADPH dehydrogenases, the alternative oxidase (AOX), and the uncoupling protein (UCP) are examined in relation to their involvement in the establishment of the stable far-from-equilibrium state of plant metabolism. The role of uncoupled respiration in controlling the levels of ROS and NO as well as inducing signaling events is considered. Secondary functions of uncoupled respiration include its role in protection from stress factors and roles in biosynthesis and catabolism. It is concluded that uncoupled mitochondrial respiration plays an important role in providing rapid adaptation of plants to changing environmental factors via regulation of ROS and NO.

scholarly journals TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
Yue Chen ◽  
Meng-huan Wang ◽  
Jian-yun Zhu ◽  
Chun-feng Xie ◽  
Xiao-ting Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Cancer Progression ◽  
Inhibitory Effect ◽  
P53 Family ◽  
First Time ◽  
Established Role

Abstract Cancer stem cells (CSCs) have an established role in cancer progression and therapeutic resistance. The p63 proteins are important transcription factors which belong to the p53 family, but their function and mechanism in CSCs remain elusive. Here, we investigated the role of TAp63α in colorectal CSCs and the effects of sulforaphane on TAp63α. We found that TAp63α was upregulated in spheres with stem cell properties compared to the parental cells. Overexpression of TAp63α promoted self-renewal capacity and enhanced CSC markers expression in colorectal sphere-forming cells. Furthermore, we showed that TAp63α directly bound to the promoter region of Lgr5 to enhance its expression and activate its downstream β-catenin pathway. Functional experiments revealed that sulforaphane suppressed the stemness of colorectal CSCs both in vitro and in vivo. Upregulation of TAp63α attenuated the inhibitory effect of sulforaphane on colorectal CSCs, indicating the role of TAp63α in sulforaphane suppression of the stemness in colorectal cancer. The present study elucidated for the first time that TAp63α promoted CSCs through targeting Lgr5/β-catenin axis and participated in sulforaphane inhibition of the stem cell properties in colorectal cancer.

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man

1995 ◽  
Vol 133 (6) ◽  
pp. 723-728 ◽  
Author(s):  
Ettore C degli Uberti ◽  
Maria R Ambrosio ◽  
Marta Bondanelli ◽  
Giorgio Transforini ◽  
Alberto Valentini ◽  
...  
Keyword(s):  
Heart Rate ◽  
Healthy Subjects ◽  
Sympathetic Nerve Activity ◽  
Heart Rate Response ◽  
Statistical Significance ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
Nerve Activity ◽  
Receptor Stimulation

degli Uberti EC, Ambrosio MR, Bondanelli M, Trasforini G, Valentini A, Rossi R, Margutti A, Campo M. Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man. Eur J Endocrinol 1995;133:723–8. ISSN 0804–4643 Human galanin (hGAL) is a neuropeptide with 30 amino acid residues that has been found in the peripheral and central nervous system, where it often co-exists with catecholamines. In order to clarify the possible role of hGAL in the regulation of sympathoadrenomedullary function, the effect of a 60 min infusion of hGAL (80 pmol·kg−1 · min−1) on plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia in nine healthy subjects was investigated. Human GAL administration significantly reduced both the release of basal norepinephrine and the response to insulin-induced hypoglycemia, whereas it attenuated the epinephrine response by 26%, with the hGAL-induced decrease in epinephrine release failing to achieve statistical significance. Human GAL significantly increased the heart rate in resting conditions and clearly exaggerated the heart rate response to insulin-induced hypoglycemia, whereas it had no effect on the blood pressure. We conclude that GAL receptor stimulation exerts an inhibitory effect on basal and insulin-induced hypoglycemia-stimulated release of norepinephrine. These findings provide further evidence that GAL may modulate sympathetic nerve activity in man but that it does not play an important role in the regulation of adrenal medullary function. Ettore C degli Uberti, Chair of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy

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