scholarly journals At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity

2021 ◽  
Vol 22 (19) ◽  
pp. 10883
Author(s):  
Dario Rizzotto ◽  
Lukas Englmaier ◽  
Andreas Villunger
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Specific Cell ◽  
Cell Type ◽  
Cell Fate Decisions

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function.

scholarly journals At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

2021 ◽  
Author(s):  
Dario Rizzotto ◽  
Lukas Englmaier ◽  
Andreas Villunger
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Specific Cell ◽  
Cell Type ◽  
Cell Fate Decisions

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may well be cell type and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered as critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview on multiple ways how p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems is critical to understand cell type specific cell fate induced by p53 upon its activation, in order to resolve the remaining mystery of its tumor suppressive function.

scholarly journals Arkadia via SNON enables NODAL-SMAD2/3 signaling effectors to transcribe different genes depending on their levels

2018 ◽  
Author(s):  
Jonathon M. Carthy ◽  
Marilia Ioannou ◽  
Vasso Episkopou
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Embryonic Stem ◽  
Null Mouse ◽  
Specific Cell ◽  
Cell Fates ◽  
Mammalian Embryo ◽  
Cell Fate Decisions ◽  
Dependent Cell ◽  
Anterior Posterior

AbstractHow cells assess levels of signaling and select to transcribe different target genes depending on the levels of activated effectors remains elusive. High NODAL-signalling levels specify anterior/head, lower specify posterior, and complete loss abolishes anterior-posterior patterning in the mammalian embryo. Here we show that cells assess NODAL-activated SMAD2 and SMAD3 (SMAD2/3) effector-levels by complex formation and pairing each effector with the co-repressor SNON, which is present in the cell before signaling. These complexes enable the E3-ubiquitin ligase Arkadia (RNF111) to degrade SNON. High SMAD2/3 levels can saturate and remove SNON, leading to derepression and activation of a subset of targets (high targets) that are highly susceptible to SNON repression. However, low SMAD2/3 levels can only reduce SNON preventing derepression/activation of high targets. Arkadia degrades SNON transiently only upon signaling exposure, leading to dynamic signaling-responses, which most likely initiate level-specific cell-fate decisions. Arkadia-null mouse embryos and Embryonic Stem Cells (ESC) cannot develop anterior tissues and head. However, SnoN/Arkadia, double-null embryos and ESCs are rescued confirming that Arkadia removes SNON, to achieve level-dependent cell-fatesOne Sentence SummarySignaling intensity induces equivalent degradation of a transcriptional repressor leading to level-dependent responses.

scholarly journals The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuko Miyazaki ◽  
Masaki Miyazaki
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Fate Decisions ◽  
Chromatin Architecture ◽  
Cell Type Specific

Cell type-specific gene expression is driven through the interplay between lineage-specific transcription factors (TFs) and the chromatin architecture, such as topologically associating domains (TADs), and enhancer-promoter interactions. To elucidate the molecular mechanisms of the cell fate decisions and cell type-specific functions, it is important to understand the interplay between chromatin architectures and TFs. Among enhancers, super-enhancers (SEs) play key roles in establishing cell identity. Adaptive immunity depends on the RAG-mediated assembly of antigen recognition receptors. Hence, regulation of the Rag1 and Rag2 (Rag1/2) genes is a hallmark of adaptive lymphoid lineage commitment. Here, we review the current knowledge of 3D genome organization, SE formation, and Rag1/2 gene regulation during B cell and T cell differentiation.

scholarly journals Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Elisa Dorantes-Acosta ◽  
Rosana Pelayo
Keyword(s):  
Cell Fate ◽  
High Efficiency ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Cell Lineage ◽  
Leukemic Cells ◽  
Acute Leukemias ◽  
Cell Fate Decisions ◽  
Lineage Switch

Acute leukemias are the most common cancer in childhood and characterized by the uncontrolled production of hematopoietic precursor cells of the lymphoid or myeloid series within the bone marrow. Even when a relatively high efficiency of therapeutic agents has increased the overall survival rates in the last years, factors such as cell lineage switching and the rise of mixed lineages at relapses often change the prognosis of the illness. During lineage switching, conversions from lymphoblastic leukemia to myeloid leukemia, or vice versa, are recorded. The central mechanisms involved in these phenomena remain undefined, but recent studies suggest that lineage commitment of plastic hematopoietic progenitors may be multidirectional and reversible upon specific signals provided by both intrinsic and environmental cues. In this paper, we focus on the current knowledge about cell heterogeneity and the lineage switch resulting from leukemic cells plasticity. A number of hypothetical mechanisms that may inspire changes in cell fate decisions are highlighted. Understanding the plasticity of leukemia initiating cells might be fundamental to unravel the pathogenesis of lineage switch in acute leukemias and will illuminate the importance of a flexible hematopoietic development.

scholarly journals Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhu-hui Yuan ◽  
Tong Liu ◽  
Hao Wang ◽  
Li-xiang Xue ◽  
Jun-jie Wang
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Ionizing Radiation ◽  
Cell Fate ◽  
Tumor Response ◽  
Cell Fate Decisions ◽  
Current Review ◽  
Pathway Crosstalk ◽  
Fatty Acids Metabolism ◽  
Molecular Signals

Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.

Cell Stress Signaling Cascades Regulating Cell Fate

2018 ◽  
Vol 24 (27) ◽  
pp. 3176-3183 ◽  
Author(s):  
Rohit Gundamaraju ◽  
Ravichandra Vemuri ◽  
Wai Chin Chong ◽  
Dominic P. Geraghty ◽  
Rajaraman Eri
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Stress Responses ◽  
Cellular Stress ◽  
Cell Stress ◽  
Signaling Cascades ◽  
Stress Signaling ◽  
Cell Type ◽  
Induce Cell Death ◽  
Stressed Cell

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

scholarly journals Neuroprotective Effect of Bergamot Juice in 6-OHDA-Induced SH-SY5Y Cell Death, an In Vitro Model of Parkinson’s Disease

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 326 ◽  
Author(s):  
Nadia Ferlazzo ◽  
Santa Cirmi ◽  
Alessandro Maugeri ◽  
Caterina Russo ◽  
Giovanni Enrico Lombardo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Nuclear Translocation ◽  
Neuroprotective Effect ◽  
Neuroblastoma Cells ◽  
Specific Cell ◽  
Protective Effects ◽  
Human Neuroblastoma

Much evidence suggests that both oxidative stress and apoptosis play a key role in the pathogenesis of Parkinson’s disease (PD). The present study aims to evaluate the protective effect of bergamot juice (BJ) against 6-hydroxydopamine (6-OHDA)- or H2O2-induced cell death. Treatment of differentiated SH-SY5Y human neuroblastoma cells with 6-OHDA or H2O2 resulted in cell death that was significantly reduced by the pre-treatment with BJ. The protective effects of BJ seem to correlate with the reduction of intracellular reactive oxygen species and nitric oxide generation caused by 6-OHDA or H2O2. BJ also attenuated mitochondrial dysfunction, caspase-3 activation, imbalance of pro- and anti-apoptotic proteins, MAPKs activation and reduced NF-ĸB nuclear translocation evoked by neurotoxic agents. Additionally, BJ exhibited excellent antioxidant capability in cell-free assays. Collectively, our results suggest that BJ exerts neuroprotective effect through the interplay with specific cell targets and its antioxidant activity, making it worthy of consideration for the management of neurodegenerative diseases.

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

United colours of chromatin? Developmental genome organisation in flies

2019 ◽  
Vol 47 (2) ◽  
pp. 691-700
Author(s):  
Caroline Delandre ◽  
Owen J. Marshall
Keyword(s):  
Cell Fate ◽  
Fruit Fly ◽  
Genome Organisation ◽  
Chromatin Protein ◽  
Cell Type ◽  
Chromatin States ◽  
Cell Fate Decisions ◽  
A Cell ◽  
Cell Type Specific ◽  
Chromatin Biology

Abstract The organisation of DNA into differing forms of packaging, or chromatin, controls many of the cell fate decisions during development. Although early studies focused on individual forms of chromatin, in the last decade more holistic studies have attempted to determine a complete picture of the different forms of chromatin present within a cell. In the fruit fly, Drosophila melanogaster, the study of chromatin states has been aided by the use of complementary and cell-type-specific techniques that profile the marks that recruit chromatin protein binding or the proteins themselves. Although many questions remain unanswered, a clearer picture of how different chromatin states affect development is now emerging, with more unusual chromatin states such as Black chromatin playing key roles. Here, we discuss recent findings regarding chromatin biology in flies.

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