scholarly journals p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Liz J. Valente ◽  
Amy Tarangelo ◽  
Albert Mao Li ◽  
Marwan Naciri ◽  
Nitin Raj ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Human Cancer ◽  
Actin Dynamics ◽  
Migration And Invasion ◽  
Wild Type ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Wide Range ◽  
Oxygen Conditions ◽  
Genome Stabilization

The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer.

scholarly journals p120catenin alteration in cancer and its role in tumour invasion

2013 ◽  
Vol 368 (1629) ◽  
pp. 20130015 ◽  
Author(s):  
Florent Peglion ◽  
Sandrine Etienne-Manneville
Keyword(s):  
Rho Gtpases ◽  
Intracellular Localization ◽  
Migration And Invasion ◽  
Cellular Processes ◽  
Tumour Spread ◽  
Classical Cadherins ◽  
Wide Range ◽  
Cancer Initiation ◽  
Transcriptional Modulators ◽  
Important Player

Since its discovery in 1989 as a substrate of the Src oncogene, p120catenin has been revealed as an important player in cancer initiation and tumour dissemination. p120catenin regulates a wide range of cellular processes such as cell–cell adhesion, cell polarity and cell proliferation and plays a pivotal role in morphogenesis, inflammation and innate immunity. The pleiotropic effects of p120catenin rely on its interactions with numerous partners such as classical cadherins at the plasma membrane, Rho-GTPases and microtubules in the cytosol and transcriptional modulators in the nucleus. Alterations of p120catenin in cancer not only concern its expression level but also its intracellular localization and can lead to both pro-invasive and anti-invasive effects. This review focuses on the p120catenin-mediated pathways involved in cell migration and invasion and discusses the potential consequences of major cancer-related p120catenin alterations with respect to tumour spread.

scholarly journals Long Noncoding RNA SOX2-OT Exacerbates Hypoxia-Induced Cardiomyocytes Injury by Regulating miR-27a-3p/TGFβR1 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Guang Yang ◽  
Chunsheng Lin
Keyword(s):  
Heart Failure ◽  
Cell Apoptosis ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Heart Diseases ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Cellular Processes ◽  
Wide Range

Background. Myocardial infarction (MI) was a severe cardiovascular disease resulted from acute, persistent hypoxia, or ischemia condition. Additionally, MI generally led to heart failure, even sudden death. A multitude of research studies proposed that long noncoding RNAs (lncRNAs) frequently participated in the regulation of heart diseases. The specific function and molecular mechanism of SOX2-OT in MI remained unclear. Aim of the Study. The current research was aimed to explore the role of SOX2-OT in MI. Methods. Bioinformatics analysis (DIANA tools and Targetscan) and a wide range of experiments (CCK-8, flow cytometry, RT-qPCR, luciferase reporter, RIP, caspase-3 activity, trans-well, and western blot assays) were adopted to investigate the function and mechanism of SOX2-OT. Results. We discovered that hypoxia treatment decreased cell viability but increased cell apoptosis. Besides, lncRNA SOX2-OT expression was upregulated in hypoxic HCMs. Hereafter, we confirmed that SOX2-OT could negatively regulate miR-27a-3p levels by directly binding with miR-27a-3p, and miR-27a-3p also could negatively regulate SOX2-OT levels. Furthermore, knockdown of SOX2-OT promoted cell proliferation, migration, and invasion, but limited cell apoptosis. However, these effects were reversed by anti-miR-27a-5p. Besides, we verified that miR-27a-3p binding with the 3′UTR of TGFBR1 and SOX2-OT regulated TGFβR1 level by collaborating with miR-27a-3p in HCMs. Eventually, rescue assays validated that the influence of SOX2-OT silence or miR-27a-3p overexpression on cellular processes in cardiomyocytes injury was counteracted by TGFBR1 overexpression. Conclusions. Long noncoding RNA SOX2-OT exacerbated hypoxia-induced cardiomyocytes injury by regulating miR-27a-3p/TGFβR1 axis, which may provide a novel insight for heart failure treatment.

BAG-1 in carcinogenesis

2004 ◽  
Vol 6 (7) ◽  
pp. 1-15 ◽  
Author(s):  
Adam Sharp ◽  
Simon J. Crabb ◽  
Ramsey I. Cutress ◽  
Matthew Brimmell ◽  
Xiu-hong Wang ◽  
...  
Keyword(s):  
Human Cancer ◽  
Predictive Marker ◽  
Nuclear Hormone Receptor ◽  
Response To Therapy ◽  
Clinical Implications ◽  
Multifunctional Protein ◽  
Cellular Processes ◽  
Wide Range ◽  
Cancer Types ◽  
And Function

BAG-1 is a multifunctional protein that exists as several differentially localised and functionally distinct isoforms. BAG-1 isoforms interact with a diverse array of molecular targets and regulate a wide range of cellular processes, including proliferation, survival, transcription, apoptosis, metastasis and motility. The BAG domain of BAG-1 interacts with chaperone molecules and this is considered important for many BAG-1 functions. The ability of BAG-1 to regulate such a wide variety of cellular processes suggests it might play an important role in many cancer types. For example, regulation of nuclear hormone receptor function and susceptibility to apoptosis might have a major impact on cancer development, progression and response to therapy. There is also increasing evidence that BAG-1 expression is altered in a variety of human malignancies relative to normal cells, and with further understanding of BAG-1 function it might become a powerful prognostic/predictive marker in human cancer. This review describes the structure and function of BAG-1 isoforms and the potential clinical implications of their expression in tumour cells.

scholarly journals A pharmacological cocktail for arresting actin dynamics in living cells

2011 ◽  
Vol 22 (21) ◽  
pp. 3986-3994 ◽  
Author(s):  
Grace E. Peng ◽  
Sarah R. Wilson ◽  
Orion D. Weiner
Keyword(s):  
Leading Edge ◽  
Actin Dynamics ◽  
Actin Assembly ◽  
Actin Reorganization ◽  
Cellular Processes ◽  
Wide Range ◽  
Morphological Polarity ◽  
Nih 3T3 ◽  
External Stimuli

The actin cytoskeleton is regulated by factors that influence polymer assembly, disassembly, and network rearrangement. Drugs that inhibit these events have been used to test the role of actin dynamics in a wide range of cellular processes. Previous methods of arresting actin rearrangements take minutes to act and work well in some contexts, but can lead to significant actin reorganization in cells with rapid actin dynamics, such as neutrophils. In this paper, we report a pharmacological cocktail that not only arrests actin dynamics but also preserves the structure of the existing actin network in neutrophil-like HL-60 cells, human fibrosarcoma HT1080 cells, and mouse NIH 3T3 fibroblast cells. Our cocktail induces an arrest of actin dynamics that initiates within seconds and persists for longer than 10 min, during which time cells maintain their responsivity to external stimuli. With this cocktail, we demonstrate that actin dynamics, and not simply morphological polarity or actin accumulation at the leading edge, are required for the spatial persistence of Rac activation in HL-60 cells. Our drug combination preserves the structure of the existing cytoskeleton while blocking actin assembly, disassembly, and rearrangement, and should prove useful for investigating the role of actin dynamics in a wide range of cellular signaling contexts.

scholarly journals Differential transcriptional reprogramming by wild type and lymphoma-associated mutant MYC proteins as B-cells convert to lymphoma-like cells

2020 ◽  
Author(s):  
Amir Mahani ◽  
Gustav Arvidsson ◽  
Laia Sadeghi ◽  
Alf Grandien ◽  
Anthony P. Wright
Keyword(s):  
B Cells ◽  
Poor Prognosis ◽  
Ribosome Biogenesis ◽  
Cell Model ◽  
Human Cancer ◽  
Hot Spot ◽  
Transactivation Domain ◽  
Wild Type ◽  
Vast Number ◽  
Wide Range

AbstractThe transcription factor MYC regulates the expression of a vast number of genes and is implicated in various human malignancies, for which it’s deregulation by genomic events such as translocation or amplification can be either disease-defining or associated with poor prognosis. In hematological malignancies MYC is frequently subject to missense mutations and one such hot spot where mutations have led to increased protein stability and elevated transformation activity exists within its transactivation domain. Here we present and characterize a model system for studying the effects of gradually increasing MYC levels as B-cells progress to lymphoma-like cells. Inclusion of two frequent lymphoma-associated MYC mutants (T58A and T58I) allowed for discrimination of changes in the MYC regulatory program according to mutation status. Progressive increase in MYC levels significantly altered the transcript levels of 7569 genes and subsets of these were regulated differently in mutant MYC proteins compared to WT MYC or between the mutant MYC proteins. Functional classification of the differentially regulated genes based on expression levels across different MYC levels confirmed previously found MYC regulated functions such as ribosome biogenesis and purine metabolism while other functional groups such as the downregulation of genes involved in B-cell differentiation and chemotaxis were novel. Gene sets that were differently regulated in cells overexpressing mutant MYC proteins contained an over-representation of genes involved in DNA Replication and transition from the G2 phase to mitosis. The cell model presented here mimics changes seen during lymphoma development in the Eμ-Myc mouse model as well as MYC-dependent events associated with poor prognosis in a wide range of human cancer types and therefore constitutes a relevant cell model for in vitro mechanistic studies of wild type and mutant MYC proteins in relation to lymphoma development.

scholarly journals p53-Mediated Tumor Suppression: DNA-Damage Response and Alternative Mechanisms

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1983 ◽  
Author(s):  
Consuelo Pitolli ◽  
Ying Wang ◽  
Eleonora Candi ◽  
Yufang Shi ◽  
Gerry Melino ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Dna Damage Response ◽  
Tumor Suppression ◽  
Migration And Invasion ◽  
Tumor Suppressor P53 ◽  
Suppressor Activity ◽  
Cellular Processes ◽  
Damage Response ◽  
Tumor Suppressor Activity

The tumor suppressor p53 regulates different cellular pathways involved in cell survival, DNA repair, apoptosis, and senescence. However, according to an increasing number of studies, the p53-mediated canonical DNA damage response is dispensable for tumor suppression. p53 is involved in mechanisms regulating many other cellular processes, including metabolism, autophagy, and cell migration and invasion, and these pathways might crucially contribute to its tumor suppressor function. In this review we summarize the canonical and non-canonical functions of p53 in an attempt to provide an overview of the potentially crucial aspects related to its tumor suppressor activity.

scholarly journals Molecular and Cellular Mechanisms Affected in ALS

2020 ◽  
Vol 10 (3) ◽  
pp. 101 ◽  
Author(s):  
Laura Le Gall ◽  
Ekene Anakor ◽  
Owen Connolly ◽  
Udaya Vijayakumar ◽  
William Duddy ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Glutamate Excitotoxicity ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Onset Condition ◽  
Wide Range ◽  
Sporadic Cases ◽  
Aberrant Rna

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

scholarly journals PakD, a Putative p21-Activated Protein Kinase in Dictyostelium discoideum, Regulates Actin

2013 ◽  
Vol 13 (1) ◽  
pp. 119-126 ◽  
Author(s):  
Miguel Garcia ◽  
Sibnath Ray ◽  
Isaiah Brown ◽  
Jon Irom ◽  
Derrick Brazill
Keyword(s):  
Protein Kinase ◽  
Actin Cytoskeleton ◽  
Dictyostelium Discoideum ◽  
Cell Function ◽  
Actin Dynamics ◽  
Wild Type ◽  
Content Type ◽  
Multicellular Development ◽  
Actin Organization ◽  
Cellular Processes

ABSTRACT Proper regulation of the actin cytoskeleton is essential for cell function and ultimately for survival. Tight control of actin dynamics is required for many cellular processes, including differentiation, proliferation, adhesion, chemotaxis, endocytosis, exocytosis, and multicellular development. Here we describe a putative p21-activated protein kinase, PakD, that regulates the actin cytoskeleton in Dictyostelium discoideum . We found that cells lacking pakD are unable to aggregate and thus unable to develop. Compared to the wild type, cells lacking PakD have decreased membrane extensions, suggesting defective regulation of the actin cytoskeleton. pakD − cells show poor chemotaxis toward cyclic AMP (cAMP) but normal chemotaxis toward folate, suggesting that PakD mediates some but not all chemotaxis responses. pakD − cells have decreased polarity when placed in a cAMP gradient, indicating that the chemotactic defects of the pakD − cells may be due to an impaired cytoskeletal response to cAMP. In addition, while wild-type cells polymerize actin in response to global stimulation by cAMP, pakD − cells exhibit F-actin depolymerization under the same conditions. Taken together, the results suggest that PakD is part of a pathway coordinating F-actin organization during development.

scholarly journals Long non-coding RNA CCDC183-AS1 acts AS a miR-589-5p sponge to promote the progression of hepatocellular carcinoma through regulating SKP1 expression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
He Zhu ◽  
Hongwei Zhang ◽  
Youliang Pei ◽  
Zhibin Liao ◽  
Furong Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Human Cancer ◽  
Quantitative Polymerase Chain Reaction ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
High Morbidity ◽  
Regulatory Relationship

Abstract Background Hepatocellular carcinoma (HCC) is a common type of malignant human cancer with high morbidity and poor prognosis, causing numerous deaths per year worldwide. Growing evidence has been demonstrated that long non-coding RNAs (lncRNAs) are closely associated with hepatocarcinogenesis and metastasis. However, the roles, functions, and working mechanisms of most lncRNAs in HCC remain poorly defined. Methods Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression level of CCDC183-AS1 in HCC tissues and cell lines. Cell proliferation, migration and invasion ability were evaluated by CCK-8 and transwell assay, respectively. Animal experiments were used to explore the role of CCDC183-AS1 and miR-589-5p in vivo. Bioinformatic analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the regulatory relationship between CCDC183-AS1, miR-589-5p and SKP1. Results Significantly upregulated expression of CCDC183-AS1 was observed in both HCC tissues and cell lines. HCC patients with higher expression of CCDC183-AS1 had a poorer overall survival rate. Functionally, overexpression of CCDC183-AS1 markedly promoted HCC cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas the downregulation of CCDC183-AS1 exerted opposite effects. MiR-589-5p inhibitor counteracted the proliferation, migration and invasion inhibitory effects induced by CCDC183-AS1 silencing. Mechanistically, CCDC183-AS1 acted as a ceRNA through sponging miR-589-5p to offset its inhibitory effect on the target gene SKP1, then promoted the tumorigenesis of HCC. Conclusions CCDC183-AS1 functions as an oncogene to promote HCC progression through the CCDC183-AS1/miR-589-5p/SKP1 axis. Our study provided a novel potential therapeutic target for HCC patients.

scholarly journals Intracellular Ionic Strength Sensing Using NanoLuc

2021 ◽  
Vol 22 (2) ◽  
pp. 677
Author(s):  
Tausif Altamash ◽  
Wesam Ahmed ◽  
Saad Rasool ◽  
Kabir H. Biswas
Keyword(s):  
Thermal Stability ◽  
Phase Separation ◽  
Drug Discovery ◽  
Ionic Strength ◽  
Cellular Signaling ◽  
Live Cells ◽  
Protein Activity ◽  
Cellular Survival ◽  
Cellular Processes ◽  
Wide Range

Intracellular ionic strength regulates myriad cellular processes that are fundamental to cellular survival and proliferation, including protein activity, aggregation, phase separation, and cell volume. It could be altered by changes in the activity of cellular signaling pathways, such as those that impact the activity of membrane-localized ion channels or by alterations in the microenvironmental osmolarity. Therefore, there is a demand for the development of sensitive tools for real-time monitoring of intracellular ionic strength. Here, we developed a bioluminescence-based intracellular ionic strength sensing strategy using the Nano Luciferase (NanoLuc) protein that has gained tremendous utility due to its high, long-lived bioluminescence output and thermal stability. Biochemical experiments using a recombinantly purified protein showed that NanoLuc bioluminescence is dependent on the ionic strength of the reaction buffer for a wide range of ionic strength conditions. Importantly, the decrease in the NanoLuc activity observed at higher ionic strengths could be reversed by decreasing the ionic strength of the reaction, thus making it suitable for sensing intracellular ionic strength alterations. Finally, we used an mNeonGreen–NanoLuc fusion protein to successfully monitor ionic strength alterations in a ratiometric manner through independent fluorescence and bioluminescence measurements in cell lysates and live cells. We envisage that the biosensing strategy developed here for detecting alterations in intracellular ionic strength will be applicable in a wide range of experiments, including high throughput cellular signaling, ion channel functional genomics, and drug discovery.

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