scholarly journals PTRH2: an adhesion regulated molecular switch at the nexus of life, death, and differentiation

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Austin D. Corpuz ◽  
Joe W. Ramos ◽  
Michelle L. Matter
Keyword(s):  
Cell Survival ◽  
Developmental Delays ◽  
Gene Mutations ◽  
Pancreatic Disease ◽  
Loss Of Function ◽  
Multisystem Disease ◽  
Cellular Processes ◽  
State Of The Science ◽  
Bcl2 Expression

AbstractPeptidyl-tRNA hydrolase 2 (PTRH2; Bit-1; Bit1) is an underappreciated regulator of adhesion signals and Bcl2 expression. Its key roles in muscle differentiation and integrin-mediated signaling are central to the pathology of a recently identified patient syndrome caused by a cluster of Ptrh2 gene mutations. These loss-of-function mutations were identified in patients presenting with severe deleterious phenotypes of the skeletal muscle, endocrine, and nervous systems resulting in a syndrome called Infantile-onset Multisystem Nervous, Endocrine, and Pancreatic Disease (IMNEPD). In contrast, in cancer PTRH2 is a potential oncogene that promotes malignancy and metastasis. PTRH2 modulates PI3K/AKT and ERK signaling in addition to Bcl2 expression and thereby regulates key cellular processes in response to adhesion including cell survival, growth, and differentiation. In this Review, we discuss the state of the science on this important cell survival, anoikis and differentiation regulator, and opportunities for further investigation and translation. We begin with a brief overview of the structure, regulation, and subcellular localization of PTRH2. We discuss the cluster of gene mutations thus far identified which cause developmental delays and multisystem disease. We then discuss the role of PTRH2 and adhesion in breast, lung, and esophageal cancers focusing on signaling pathways involved in cell survival, cell growth, and cell differentiation.

The role of hypoxia in endometrial cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Yarely M. Salinas-Vera ◽  
Dolores Gallardo-Rincón ◽  
Erika Ruíz-García ◽  
Macrina B. Silva-Cázares ◽  
Carmen Sol de la Peña-Cruz ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Targeted Therapies ◽  
Current Knowledge ◽  
Vasculogenic Mimicry ◽  
Cellular Processes ◽  
Corpus Uteri

: Endometrial cancer represents the most frequent neoplasia from the corpus uteri, and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance urged to ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors from breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

scholarly journals Dynamic measurement of cytosolic pH and [NO3−] uncovers the role of the vacuolar transporter AtCLCa in cytosolic pH homeostasis

2020 ◽  
Vol 117 (26) ◽  
pp. 15343-15353 ◽  
Author(s):  
Elsa Demes ◽  
Laetitia Besse ◽  
Paloma Cubero-Font ◽  
Béatrice Satiat-Jeunemaitre ◽  
Sébastien Thomine ◽  
...  
Keyword(s):  
Chloride Channel ◽  
Loss Of Function ◽  
Ion Transporters ◽  
Ph Homeostasis ◽  
Cytosolic Ph ◽  
Cellular Processes ◽  
Plasma Membrane Proton Pump ◽  
Cytosolic Acidification

Ion transporters are key players of cellular processes. The mechanistic properties of ion transporters have been well elucidated by biophysical methods. Meanwhile, the understanding of their exact functions in cellular homeostasis is limited by the difficulty of monitoring their activity in vivo. The development of biosensors to track subtle changes in intracellular parameters provides invaluable tools to tackle this challenging issue. AtCLCa (Arabidopsis thalianaChloride Channel a) is a vacuolar NO3−/H+exchanger regulating stomata aperture inA.thaliana. Here, we used a genetically encoded biosensor, ClopHensor, reporting the dynamics of cytosolic anion concentration and pH to monitor the activity of AtCLCa in vivo inArabidopsisguard cells. We first found that ClopHensor is not only a Cl−but also, an NO3−sensor. We were then able to quantify the variations of NO3−and pH in the cytosol. Our data showed that AtCLCa activity modifies cytosolic pH and NO3−. In an AtCLCa loss of function mutant, the cytosolic acidification triggered by extracellular NO3−and the recovery of pH upon treatment with fusicoccin (a fungal toxin that activates the plasma membrane proton pump) are impaired, demonstrating that the transport activity of this vacuolar exchanger has a profound impact on cytosolic homeostasis. This opens a perspective on the function of intracellular transporters of the Chloride Channel (CLC) family in eukaryotes: not only controlling the intraorganelle lumen but also, actively modifying cytosolic conditions.

scholarly journals Beneficial Role of ROS in Cell Survival: Moderate Increases in H2O2 Production Induced by Hepatocyte Isolation Mediate Stress Adaptation and Enhanced Survival

Antioxidants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 434 ◽  
Author(s):  
Izak Patrik Miller ◽  
Ivan Pavlović ◽  
Borut Poljšak ◽  
Dušan Šuput ◽  
Irina Milisav
Keyword(s):  
Cell Survival ◽  
Cell Structure ◽  
Fold Increase ◽  
Mitochondrial Pathway ◽  
Stress Adaptation ◽  
H2o2 Production ◽  
Loss Of Function ◽  
Isolated Cells ◽  
Hepatocyte Isolation

High levels of reactive oxygen species (ROS) can lead to impairment of cell structure, biomolecules’ loss of function and cell death and are associated with liver diseases. Cells that survive increased ROS often undergo malignant transformation. Many cancer cells tolerate high levels of ROS. Here we report a transiently increased production of H2O2 and concomitant upregulation of antioxidative enzymes triggered by hepatocyte isolation; the H2O2 levels revert in about two days in culture. Three-day survival rate of the isolated cells in the presence of 2.5-fold increase of H2O2 is almost 80%. Apoptosis activation through the mitochondrial pathway is meanwhile reduced by inhibition of caspase-9 triggering. This reduction depends on the amount of H2O2 production, as decreased production of H2O2 in the presence of an antioxidant results in increased apoptosis triggering. These stress adaptations do not influence urea production, which is unchanged throughout the normal and stress adapted phases. We conclude that hepatocytes’ stress adaptation is mediated by increased ROS production. In this case, high ROS improve cell survival.

scholarly journals Active regulator of SIRT1 is required for cancer cell survival but not for SIRT1 activity

Open Biology ◽  
2013 ◽  
Vol 3 (11) ◽  
pp. 130130 ◽  
Author(s):  
John R. P. Knight ◽  
Simon J. Allison ◽  
Jo Milner
Keyword(s):  
Cell Survival ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Survival ◽  
Cancer Cell Lines ◽  
Cellular Processes ◽  
Disease States ◽  
Cancer Cell Survival ◽  
P53 Activation

The NAD + -dependent deacetylase SIRT1 is involved in diverse cellular processes, and has also been linked with multiple disease states. Among these, SIRT1 expression negatively correlates with cancer survival in both laboratory and clinical studies. Active regulator of SIRT1 (AROS) was the first reported post-transcriptional regulator of SIRT1 activity, enhancing SIRT1-mediated deacetylation and downregulation of the SIRT1 target p53. However, little is known regarding the role of AROS in regulation of SIRT1 during disease. Here, we report the cellular and molecular effects of RNAi-mediated AROS suppression, comparing this with the role of SIRT1 in a panel of human cell lines of both cancerous and non-cancerous origins. Unexpectedly, AROS is found to vary in its modulation of p53 acetylation according to cell context. AROS suppresses p53 acetylation only following the application of cell damaging stress, whereas SIRT1 suppresses p53 under all conditions analysed. This supplements the original characterization of AROS but indicates that SIRT1 activity can persist following suppression of AROS. We also demonstrate that knockdown of AROS induces apoptosis in three cancer cell lines, independent of p53 activation. Importantly, AROS is not required for the viability of three non-cancer cell lines indicating a putative role for AROS in specifically promoting cancer cell survival.

The role of the zinc transporter SLC30A2/ZnT2 in transient neonatal zinc deficiency

Metallomics ◽  
2017 ◽  
Vol 9 (10) ◽  
pp. 1352-1366 ◽  
Author(s):  
Yarden Golan ◽  
Taiho Kambe ◽  
Yehuda G. Assaraf
Keyword(s):  
Zinc Deficiency ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Zinc Transporter ◽  
Loss Of Function ◽  
Breastfed Infants ◽  
Nursing Mothers ◽  
Novel Approaches

Transient neonatal zinc deficiency (TNZD) results from loss of function mutations in theSLC30A2/ZnT2gene. Nursing mothers harboring this defective zinc transporter produce zinc-deficient milk. Consequently, their exclusively breastfed infants develop severe zinc deficiency. The present review summarizes our current knowledge onSLC30A2/ZnT2gene mutations and highlights the molecular mechanisms underlying this zinc deficiency. We further propose novel approaches for the early diagnosis and prevention of TNZD.

scholarly journals Usp14 is required for spermatogenesis and ubiquitin stress responses in Drosophila melanogaster

2019 ◽  
Author(s):  
Levente Kovács ◽  
Ágota Nagy ◽  
Margit Pál ◽  
Peter Deák
Keyword(s):  
Male Sterility ◽  
Stress Responses ◽  
Expression Patterns ◽  
Loss Of Function ◽  
Wild Type ◽  
Cellular Processes ◽  
Protein Conjugates ◽  
Covalently Linked ◽  
Mutant Phenotypes

ABSTRACTDeubiquitinating (DUB) enzymes free covalently linked ubiquitins from ubiquitin-ubiquitin and ubiquitin-protein conjugates, and thereby maintain the equilibrium between free and conjugated ubiquitins and regulate ubiquitin-mediated cellular processes. The present genetic analyses of mutant phenotypes demonstrate that loss of Usp14 function results in male sterility, with defects in spermatid individualization and reduced testicular free monoubiquitin levels. These phenotypes were rescued by germline specific overexpression of wild type Usp14. Synergistic genetic interactions with Ubi-p63E and cycloheximide sensitivity suggest that ubiquitin shortage is a primary cause of male sterility. In addition, Usp14 is predominantly expressed in testes in Drosophila, and differential expression patterns may be causative of testis-specific loss of function Usp14 phenotypes. Collectively, these results suggest a major role of Usp14 in maintaining normal steady state free monoubiquitin levels during the later stages of Drosophila spermatogenesis.

scholarly journals Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

2020 ◽  
Author(s):  
Zeina R Al Sayed ◽  
Robin Canac ◽  
Bastien Cimarosti ◽  
Carine Bonnard ◽  
Jean-Baptiste Gourraud ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Electrical Conduction ◽  
Sodium Current ◽  
Single Gene ◽  
Gene Mutations ◽  
Cardiac Conduction ◽  
Human Model ◽  
Loss Of Function ◽  
Cardiac Electrical Activity

Abstract Aims Several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Methods and results Using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Conclusion Altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases.

scholarly journals Genetically-induced Redox Stress Occurs in a Yeast Model for Roberts Syndrome

2021 ◽  
Author(s):  
Michael G Mfarej ◽  
Robert V Skibbens
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Gene Mutations ◽  
Loss Of Function ◽  
Redox Stress ◽  
Cellular Processes ◽  
Transcriptional Dysregulation ◽  
Dna Damaging Agents ◽  
Roberts Syndrome ◽  
Mutant Cells

Abstract Roberts Syndrome (RBS) is a multi-spectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for Roberts Syndrome and tumors that bear ESCO2 mutations.

Exploiting S-nitrosylation for cancer therapy: facts and perspectives

2020 ◽  
Vol 477 (19) ◽  
pp. 3649-3672
Author(s):  
Salvatore Rizza ◽  
Giuseppe Filomeni
Keyword(s):  
Nitric Oxide ◽  
Cancer Biology ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Tissue Homeostasis ◽  
Loss Of Function ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Insight Into

S-nitrosylation, the post-translational modification of cysteines by nitric oxide, has been implicated in several cellular processes and tissue homeostasis. As a result, alterations in the mechanisms controlling the levels of S-nitrosylated proteins have been found in pathological states. In the last few years, a role in cancer has been proposed, supported by the evidence that various oncoproteins undergo gain- or loss-of-function modifications upon S-nitrosylation. Here, we aim at providing insight into the current knowledge about the role of S-nitrosylation in different aspects of cancer biology and report the main anticancer strategies based on: (i) reducing S-nitrosylation-mediated oncogenic effects, (ii) boosting S-nitrosylation to stimulate cell death, (iii) exploiting S-nitrosylation through synthetic lethality.

The role of conserved residues in the catalytic activity of NDM-1: an approach involving site directed mutagenesis and molecular dynamics

2019 ◽  
Vol 21 (32) ◽  
pp. 17821-17835 ◽  
Author(s):  
Abid Ali ◽  
Rakesh Kumar ◽  
Mir Asif Iquebal ◽  
Sarika Jaiswal ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Catalytic Activity ◽  
Cell Survival ◽  
Conformational Changes ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Loss Of Function ◽  
Conserved Residues

Drug degraded by enzyme and hence not targeted on to the cell leading to cell survival. After mutation leading to conformational changes and loss of function hence drug was not degraded and remained available for the target to lyse the cell.

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