scholarly journals Nuclear iASPP determines cell fate by selectively inhibiting either p53 or NF-κB

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wenjie Ge ◽  
Yudong Wang ◽  
Shanliang Zheng ◽  
Dong Zhao ◽  
Xingwen Wang ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Response ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Functional Interaction ◽  
Signaling Systems ◽  
Optimal Outcomes ◽  
A Cell ◽  
Response To Stress ◽  
Biological Outcomes

Abstractp53 and NF-κBp65 are essential transcription factors (TFs) in the cellular response to stress. Two signaling systems can often be entwined together and generally produce opposing biological outcomes in a cell context-dependent manner. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) has the potential to inhibit both p53 and NF-κBp65, yet how such activities of iASPP are integrated with cancer remains unknown. Here, we utilized different cell models with diverse p53/NF-κBp65 activities. An iASPP(295–828) mutant, which is exclusively located in the nucleus and has been shown to be essential for its inhibitory effects on p53/NF-κBp65, was used to investigate the functional interaction between iASPP and the two TFs. The results showed that iASPP inhibits apoptosis under conditions when p53 is activated, while it can also elicit a proapoptotic effect when NF-κBp65 alone is activated. Furthermore, we demonstrated that iASPP inhibited the transcriptional activity of p53/NF-κBp65, but with a preference toward p53, thereby producing an antiapoptotic outcome when both TFs were simultaneously activated. This may be due to stronger binding between p53 and iASPP than NF-κBp65 and iASPP. Overall, these findings provide important insights into how the activities of p53 and NF-κBp65 are modulated by iASPP. Despite being a well-known oncogene, iASPP may have a proapoptotic role, which will guide the development of iASPP-targeted therapies to reach optimal outcomes in the future.

scholarly journals p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner

PLoS ONE ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. e3707 ◽  
Author(s):  
Alina Molchadsky ◽  
Igor Shats ◽  
Naomi Goldfinger ◽  
Meirav Pevsner-Fischer ◽  
Melissa Olson ◽  
...  
Keyword(s):  
Cell Fate ◽  
Dependent Manner ◽  
Mesenchymal Differentiation ◽  
A Cell

scholarly journals Regardless of the deposition pathway, aminoacid 31 in histone variant H3 is essential at gastrulation in Xenopus

2019 ◽  
Author(s):  
David Sitbon ◽  
Ekaterina Boyarchuk ◽  
Geneviève Almouzni
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Unique Property ◽  
Dependent Manner ◽  
Critical Importance ◽  
Distinct Mode ◽  
Developmental Defects ◽  
A Cell ◽  
Cycle Dependent ◽  
Conserved Residue

AbstractThe closely related replicative H3 and non-replicative H3.3 variants show specific requirement during development in vertebrates. Whether it involves distinct mode of deposition or unique roles once incorporated into chromatin remains unclear. To disentangle the two aspects, we took advantage of the Xenopus early development combined with chromatin assays. Our previous work showed that in Xenopus, depletion of the non-replicative variant H3.3 impairs development at gastrulation, without compensation through provision of the replicative variant H3.2. We systematically mutated H3.3 at each four residues that differ from H3.2 and tested their ability to rescue developmental defects. Surprisingly, all H3.3 mutated variants functionally complemented endogenous H3.3, regardless of their incorporation pathways, except for one residue. This particular residue, the serine at position 31 in H3.3, gets phosphorylated onto chromatin in a cell cycle dependent manner. While the alanine substitution failed to rescue H3.3 depletion, a phosphomimic residue sufficed. We conclude that the time of gastrulation reveals a critical importance of the H3.3S31 residue independently of the variant incorporation pathway. We discuss how this single evolutionary conserved residue conveys a unique property for this variant in vertebrates during cell cycle and cell fate commitment.

scholarly journals Opposing effects of Wnt/β-catenin signaling on epithelial and mesenchymal cell fate in the developing cochlea

Development ◽  
2021 ◽  
Vol 148 (11) ◽  
Author(s):  
Sara E. Billings ◽  
Nina M. Myers ◽  
Lee Quiruz ◽  
Alan G. Cheng
Keyword(s):  
Cell Fate ◽  
Mesenchymal Cell ◽  
Lateral Wall ◽  
Mesenchymal Cells ◽  
Sensory Cells ◽  
Dependent Manner ◽  
Cell Fates ◽  
Proliferation And Differentiation ◽  
A Cell ◽  
Opposing Effects

ABSTRACT During embryonic development, the otic epithelium and surrounding periotic mesenchymal cells originate from distinct lineages and coordinate to form the mammalian cochlea. Epithelial sensory precursors within the cochlear duct first undergo terminal mitosis before differentiating into sensory and non-sensory cells. In parallel, periotic mesenchymal cells differentiate to shape the lateral wall, modiolus and pericochlear spaces. Previously, Wnt activation was shown to promote proliferation and differentiation of both otic epithelial and mesenchymal cells. Here, we fate-mapped Wnt-responsive epithelial and mesenchymal cells in mice and found that Wnt activation resulted in opposing cell fates. In the post-mitotic cochlear epithelium, Wnt activation via β-catenin stabilization induced clusters of proliferative cells that dedifferentiated and lost epithelial characteristics. In contrast, Wnt-activated periotic mesenchyme formed ectopic pericochlear spaces and cell clusters showing a loss of mesenchymal and gain of epithelial features. Finally, clonal analyses via multi-colored fate-mapping showed that Wnt-activated epithelial cells proliferated and formed clonal colonies, whereas Wnt-activated mesenchymal cells assembled as aggregates of mitotically quiescent cells. Together, we show that Wnt activation drives transition between epithelial and mesenchymal states in a cell type-dependent manner.

scholarly journals Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

2017 ◽  
Vol 114 (37) ◽  
pp. 9948-9953 ◽  
Author(s):  
Andrea Vettori ◽  
David Greenald ◽  
Garrick K. Wilson ◽  
Margherita Peron ◽  
Nicola Facchinello ◽  
...  
Keyword(s):  
Cross Talk ◽  
Cellular Response ◽  
Isolated Hepatocytes ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Transcriptional Responses ◽  
Human Liver Tissue ◽  
Von Hippel Lindau ◽  
Response To Stress

Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src–mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL.

scholarly journals Cell fate determined by the activation balance between PKR and SPHK1

2020 ◽  
Vol 28 (1) ◽  
pp. 401-418
Author(s):  
Han Qiao ◽  
Tianqing Jiang ◽  
Peiqiang Mu ◽  
Xiaoxuan Chen ◽  
Xianhui Wen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Cellular Response ◽  
Cellular Stress Response ◽  
Protein Kinase R ◽  
Survival Pathways ◽  
Stress Signal ◽  
Dependent Protein ◽  
Response To Stress ◽  
Simultaneous Activation

AbstractDouble-stranded RNA (dsRNA)-dependent protein kinase R (PKR) activation via autophosphorylation is the central cellular response to stress that promotes cell death or apoptosis. However, the key factors and mechanisms behind the simultaneous activation of pro-survival signaling pathways remain unknown. We have discovered a novel regulatory mechanism for the maintenance of cellular homeostasis that relies on the phosphorylation interplay between sphingosine kinase 1 (SPHK1) and PKR during exogenous stress. We identified SPHK1 as a previously unrecognized PKR substrate. Phosphorylated SPHK1, a central kinase, mediates the activation of PKR-induced pro-survival pathways by the S1P/S1PR1/MAPKs/IKKα signal axis, and antagonizes PKR-mediated endoplasmic reticulum (ER) stress signal transduction under stress conditions. Otherwise, phosphorylated SPHK1 also acts as the negative feedback factor, preferentially binding to the latent form of PKR at the C-terminal kinase motif, inhibiting the homodimerization of PKR, suppressing PKR autophosphorylation, and reducing the signaling strength for cell death and apoptosis. Our results suggest that the balance of the activation levels between PKR and SPHK1, a probable hallmark of homeostasis maintenance, determines cell fate during cellular stress response.

scholarly journals Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

2021 ◽  
Vol 22 (22) ◽  
pp. 12232
Author(s):  
Nathalie Thorin-Trescases ◽  
Pauline Labbé ◽  
Pauline Mury ◽  
Mélanie Lambert ◽  
Eric Thorin
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Age Related ◽  
A Cell ◽  
Future Work ◽  
The Impact

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

scholarly journals PML Bodies in Mitosis

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 893 ◽  
Author(s):  
Anna Lång ◽  
Emma Lång ◽  
Stig Ove Bøe
Keyword(s):  
Cell Fate ◽  
Cell Cycle Progression ◽  
Nuclear Material ◽  
Promyelocytic Leukemia ◽  
Cycle Progression ◽  
Nuclear Exclusion ◽  
Pml Bodies ◽  
A Cell ◽  
Response To Stress ◽  
Fate Decision

Promyelocytic leukemia (PML) bodies are dynamic intracellular structures that recruit and release a variety of different proteins in response to stress, virus infection, DNA damage and cell cycle progression. While PML bodies primarily are regarded as nuclear compartments, they are forced to travel to the cytoplasm each time a cell divides, due to breakdown of the nuclear membrane at entry into mitosis and subsequent nuclear exclusion of nuclear material at exit from mitosis. Here we review the biochemical and biophysical transitions that occur in PML bodies during mitosis and discuss this in light of post-mitotic nuclear import, cell fate decision and acute promyelocytic leukemia therapy.

Telomeres and Aging

2008 ◽  
Vol 88 (2) ◽  
pp. 557-579 ◽  
Author(s):  
Geraldine Aubert ◽  
Peter M. Lansdorp
Keyword(s):  
Telomere Length ◽  
Cell Fate ◽  
Cellular Response ◽  
Genome Instability ◽  
Somatic Cells ◽  
Growth Stimulation ◽  
Dyskeratosis Congenita ◽  
Telomere Attrition ◽  
Response To Stress

Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must “cap” each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or “uncapped” telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many “uncapped” telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.

scholarly journals Near-Cognate Codons Contribute Complexity to Translation Regulation

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
N. Louise Glass
Keyword(s):  
Protein Synthesis ◽  
Cell Fate ◽  
Translation Initiation ◽  
Cellular Response ◽  
Open Reading Frames ◽  
Translation Regulation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Upstream Open Reading Frames ◽  
Response To Stress

ABSTRACT The interplay between translation initiation, modification of translation initiation factors, and selection of start sites on mRNA for protein synthesis can play a regulatory role in the cellular response to stress, development, and cell fate in eukaryotic species by shaping the proteome. As shown by Ivanov et al. (mBio 8:e00844-17, 2017, https://doi.org/10.1128/mBio.00844-17 !), in the filamentous fungus Neurospora crassa, both upstream open reading frames (uORFs) and near-cognate start codons negatively or positively regulate the translation of the transcription factor CPC1 and production of CPC1 isoforms, which mediate the cellular response to amino acid starvation. Dissecting the physiological roles that differentiate cellular choice of translation initiation is an important parameter to understanding mechanisms that determine cell fate via gene regulation and protein synthesis.

scholarly journals SOL1 and SOL2 Regulate Fate Transition and Cell Divisions in the Arabidopsis Stomatal Lineage

2018 ◽  
Author(s):  
Abigail R. Simmons ◽  
Kelli A. Davies ◽  
Wanpeng Wang ◽  
Zhongchi Liu ◽  
Dominique C. Bergmann
Keyword(s):  
Cell Fate ◽  
Stomatal Density ◽  
Leaf Size ◽  
Dependent Manner ◽  
Cell Divisions ◽  
Guard Mother Cell ◽  
Stomatal Guard Cells ◽  
A Cell ◽  
Cycle Dependent ◽  
Stomatal Lineage

AbstractIn the stomatal lineage, cells make fate transitions from asymmetrically dividing and self-renewing meristemoids, to commitment to the guard mother cell identity, and finally though a single division to create mature, post-mitotic stomatal guard cells. Flexibility in the stomatal lineage allows plants to alter leaf size and stomatal density in response to environmental conditions; however, transitions must be clean and unidirectional in order to produce functional and correctly patterned stomata. Among direct transcriptional targets of the stomatal initiating factor, SPEECHLESS, we found a pair of genes, SOL1 and SOL2, required for effective transitions in the lineage. Here we show that these two genes, which are homologues of the LIN54 DNA-binding components of the mammalian DREAM complex, are expressed in a cell cycle dependent manner and regulate cell fate and division properties in the self-renewing early lineage. In the terminal division of the stomatal lineage, however, these two proteins appear to act in opposition to their closest paralogue, TSO1, revealing complexity in the gene family may enable customization of cell divisions in coordination with development.

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