scholarly journals Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Frédéric Bonnet ◽  
Angie Molina ◽  
Mélanie Roussat ◽  
Manon Azais ◽  
Sophie Bel-Vialar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Neural Progenitors ◽  
Apical Surface ◽  
Independent Function ◽  
M Cell ◽  
Stem Cell Maintenance ◽  
A Cell ◽  
Cell Cycle Dynamics ◽  
Cell Cycle Length

A fundamental issue in developmental biology and in organ homeostasis is understanding the molecular mechanisms governing the balance between stem cell maintenance and differentiation into a specific lineage. Accumulating data suggest that cell cycle dynamics play a major role in the regulation of this balance. Here we show that the G2/M cell cycle regulator CDC25B phosphatase is required in mammals to finely tune neuronal production in the neural tube. We show that in chick neural progenitors, CDC25B activity favors fast nuclei departure from the apical surface in early G1, stimulates neurogenic divisions and promotes neuronal differentiation. We design a mathematical model showing that within a limited period of time, cell cycle length modifications cannot account for changes in the ratio of the mode of division. Using a CDC25B point mutation that cannot interact with CDK, we show that part of CDC25B activity is independent of its action on the cell cycle.

scholarly journals Neurogenic decisions require a cell cycle independent function of the CD25B phosphatase

2017 ◽  
Author(s):  
Frédéric Bonnet ◽  
Mélanie Roussat ◽  
Angie Molina ◽  
Manon Azais ◽  
Sophie Belvialar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Neural Progenitors ◽  
Fundamental Issue ◽  
Independent Function ◽  
M Cell ◽  
Stem Cell Maintenance ◽  
A Cell ◽  
Cell Cycle Dynamics ◽  
Cell Cycle Length

ABSTRACTA fundamental issue in developmental biology and in organ homeostasis is understanding the molecular mechanisms governing the balance between stem cell maintenance and differentiation into a specific lineage. Accumulating data suggest that cell cycle dynamics plays a major role in the regulation of this balance. Here we show that the G2/M cell cycle regulator CDC25B phosphatase is required in mammals to finely tune neuronal production in the neural tube. We show that in chick neural progenitors, CDC25B activity is both required and sufficient to stimulate neurogenic divisions and to promote neuronal differentiation. We design a mathematical model showing that within a limited period of time, cell cycle length modifications cannot account for changes in the ratio of the mode of division. Using a CDC25B point mutation that cannot interact with CDK, we show that part of CDC25B activity on neurogenic divisions is independent of its action on the cell cycle.

Pisosterol Induces G2/M Cell Cycle Arrest and Apoptosis via the ATM/ATR Signaling Pathway in Human Glioma Cells

2020 ◽  
Vol 20 (6) ◽  
pp. 734-750
Author(s):  
Wallax A.S. Ferreira ◽  
Rommel R. Burbano ◽  
Claudia do Ó. Pessoa ◽  
Maria L. Harada ◽  
Bárbara do Nascimento Borges ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Glioma Cell ◽  
Molecular Mechanisms ◽  
Glioma Cells ◽  
Dependent Manner ◽  
M Cell ◽  
Trypan Blue Exclusion ◽  
Cycle Arrest

Background: Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific effects on glioma cells remain unknown. Objective: This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines. Methods: The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR). Results: Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53. Conclusions: It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.

scholarly journals Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

2020 ◽  
Author(s):  
Connor Rogerson ◽  
Samuel Ogden ◽  
Edward Britton ◽  
Yeng Ang ◽  
Andrew D. Sharrocks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
Chromatin Accessibility ◽  
Oesophageal Adenocarcinoma ◽  
Cell Cycle Gene ◽  
A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

scholarly journals Gcn5-mediated acetylation at MBF-regulated promoters induces the G1/S transcriptional wave

2019 ◽  
Vol 47 (16) ◽  
pp. 8439-8451 ◽  
Author(s):  
Alberto González-Medina ◽  
Elena Hidalgo ◽  
José Ayté
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Histone H3 ◽  
Dependent Manner ◽  
Saga Complex ◽  
Lysine Residues ◽  
Physical Barriers ◽  
A Cell ◽  
Cycle Dependent ◽  
Regulated Promoters

Abstract In fission yeast, MBF-dependent transcription is inactivated at the end of S phase through a negative feedback loop that involves the co-repressors, Yox1 and Nrm1. Although this repression system is well known, the molecular mechanisms involved in MBF activation remain largely unknown. Compacted chromatin constitutes a barrier to activators accessing promoters. Here, we show that chromatin regulation plays a key role in activating MBF-dependent transcription. Gcn5, a part of the SAGA complex, binds to MBF-regulated promoters through the MBF co-activator Rep2 in a cell cycle-dependent manner and in a reverse correlation to the binding of the MBF co-repressors, Nrm1 or Yox1. We propose that the co-repressors function as physical barriers to SAGA recruitment onto MBF promoters. We also show that Gcn5 acetylates specific lysine residues on histone H3 in a cell cycle-regulated manner. Furthermore, either in a gcn5 mutant or in a strain in which histone H3 is kept in an unacetylated form, MBF-dependent transcription is downregulated. In summary, Gcn5 is required for the full activation and correct timing of MBF-regulated gene transcription.

scholarly journals Lengthening the G1 Phase of Neural Progenitor Cells is Concurrent with An Increase of Symmetric Neuron Generating Division after Stroke

2007 ◽  
Vol 28 (3) ◽  
pp. 602-611 ◽  
Author(s):  
Rui L Zhang ◽  
Zheng G Zhang ◽  
Cynthia Roberts ◽  
Yvonne LeTourneau ◽  
Mei Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cycle Length ◽  
Neural Progenitor Cells ◽  
Neural Progenitors ◽  
Adult Rats ◽  
Neuronal Marker ◽  
Daughter Cells ◽  
P Fraction ◽  
Labeling Scheme ◽  
Cell Cycle Length

The proportion of neural progenitors that remain in ( P fraction) and exit from ( Q fraction) the cell cycle determines the degree of neurogenesis. Using S-phase labeling with 5-bromo-2′-deoxyuridine and a double nucleoside analog-labeling scheme, we measured the cell-cycle kinetics of neural progenitors and estimated the proportion of P and Q fractions in the subventricular zone (SVZ) of adult rats subjected to stroke. Stroke increased SVZ cell proliferation, starting 2 days, reaching a maximum 4 and 7 days after stroke. The cell-cycle length ( TC) of SVZ cells changed dynamically over a period of 2 to 14 days after stroke, with the shortest length of 11 h at 2 days after stroke. The reduction of the TC resulted from a decrease of the G1 phase because the G2, M, and S phases were unchanged. In addition, during this period, reduction of the G1 phase was concomitant with an increase in the P fraction, whereas an augmentation of the Q fraction was associated with lengthening of the G1 phase. Furthermore, approximately 90% of cells that exited the cell cycle were neurons and the population of a pair of dividing daughter cells with a neuronal marker increased from 9% at 2 days to 26% at 14 days after stroke. These data suggest that stroke triggers early expansion of the progenitor pool via shortening the cell-cycle length and retaining daughter cells within the cell cycle, and the lengthening of G1 leads to daughter cells exiting the cell cycle and differentiating into neurons.

scholarly journals Cell cycle dynamics of human pluripotent stem cells primed for differentiation

2019 ◽  
Author(s):  
Anna Shcherbina ◽  
Jingling Li ◽  
Cyndhavi Narayanan ◽  
William Greenleaf ◽  
Anshul Kundaje ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Expression Patterns ◽  
Human Pluripotent Stem Cells ◽  
Specific Manner ◽  
A Cell ◽  
Cell Cycle Dynamics ◽  
Differentiation Gene ◽  
Cycle Indicator

Understanding the molecular properties of the cell cycle of human pluripotent stem cells (hPSCs) is critical for effectively promoting differentiation. Here, we use the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) system adapted into hPSCs and perform RNA-sequencing on cell cycle sorted hPSCs primed and unprimed for differentiation. Gene expression patterns of signaling factors and developmental regulators change in a cell cycle-specific manner in cells primed for differentiation without altering genes associated with pluripotency. Furthermore, we identify an important role for PI3K signaling in regulating the early transitory states of hPSCs towards differentiation.

scholarly journals Author response: Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase

2018 ◽  
Author(s):  
Frédéric Bonnet ◽  
Angie Molina ◽  
Mélanie Roussat ◽  
Manon Azais ◽  
Sophie Bel-Vialar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Author Response ◽  
Independent Function ◽  
A Cell

scholarly journals Correction: Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Frédéric Bonnet ◽  
Angie Molina ◽  
Melanie Roussat ◽  
Manon Azais ◽  
Sophie Bel-Vialar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Independent Function ◽  
A Cell

scholarly journals Control of G2 phase duration by CDC25B modulates the switch from direct to indirect neurogenesis in the neocortex

2021 ◽  
Author(s):  
Melanie Roussat ◽  
Thomas Jungas ◽  
Christophe Audouard ◽  
Francois Medevielle ◽  
Alice Davy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cortical Neurons ◽  
Cortical Slice ◽  
Phase Duration ◽  
Basal Progenitor ◽  
Proper Number ◽  
A Cell ◽  
G2 Phase ◽  
Cell Cycle Length

During development, cortical neurons are produced in a temporally regulated sequence from apical progenitors, directly, or indirectly through the production of intermediate basal progenitors. The balance between these major progenitors types is determinant for the production of the proper number and types of neurons and it is thus important to decipher the cellular and molecular cues controlling this equilibrium. Here we address the role of a cell cycle regulator, the CDC25B phosphatase, in this process. We show that deleting CDC25B in apical progenitors leads to a transient increase of the production of TBR1+ neurons at the expense of TBR2+ basal progenitors in mouse neocortex. This phenotype is associated with lengthening of the G2 phase of the cell cycle, the total cell cycle length being unaffected. Using in utero electroporation and cortical slice cultures, we demonstrate that the defect in TBR2+ basal progenitor production requires interaction with CDK1 and is due to the G2 phase lengthening in CDC25B mutants. Altogether, this study identifies a new role for CDC25B and the length of the G2 phase in direct versus indirect neurogenesis at early stages of the cortical development.

scholarly journals Let-7 regulates cell cycle dynamics in the developing cerebral cortex and retina

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Corinne L. A. Fairchild ◽  
Simranjeet K. Cheema ◽  
Joanna Wong ◽  
Keiko Hino ◽  
Sergi Simó ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Developmental Time ◽  
Neural Progenitors ◽  
Cycle Progression ◽  
Cell Fate Decisions ◽  
Cell Cycle Dynamics

Abstract In the neural progenitors of the developing central nervous system (CNS), cell proliferation is tightly controlled and coordinated with cell fate decisions. Progenitors divide rapidly during early development and their cell cycle lengthens progressively as development advances to eventually give rise to a tissue of the correct size and cellular composition. However, our understanding of the molecules linking cell cycle progression to developmental time is incomplete. Here, we show that the microRNA (miRNA) let-7 accumulates in neural progenitors over time throughout the developing CNS. Intriguingly, we find that the level and activity of let-7 oscillate as neural progenitors progress through the cell cycle by in situ hybridization and fluorescent miRNA sensor analyses. We also show that let-7 mediates cell cycle dynamics: increasing the level of let-7 promotes cell cycle exit and lengthens the S/G2 phase of the cell cycle, while let-7 knock down shortens the cell cycle in neural progenitors. Together, our findings suggest that let-7 may link cell proliferation to developmental time and regulate the progressive cell cycle lengthening that occurs during development.

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