scholarly journals Cell cycle arrest determines adult neural stem cell ontogeny by an embryonic Notch-nonoscillatory Hey1 module

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yujin Harada ◽  
Mayumi Yamada ◽  
Itaru Imayoshi ◽  
Ryoichiro Kageyama ◽  
Yutaka Suzuki ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Adult Neural Stem Cell ◽  
Cycle Arrest ◽  
Adult Nscs ◽  
Neural Stem Progenitor Cells ◽  
The Brain ◽  
Term Maintenance

AbstractQuiescent neural stem cells (NSCs) in the adult mouse brain are the source of neurogenesis that regulates innate and adaptive behaviors. Adult NSCs in the subventricular zone are derived from a subpopulation of embryonic neural stem-progenitor cells (NPCs) that is characterized by a slower cell cycle relative to the more abundant rapid cycling NPCs that build the brain. Yet, how slow cell cycle can cause the establishment of adult NSCs remains largely unknown. Here, we demonstrate that Notch and an effector Hey1 form a module that is upregulated by cell cycle arrest in slowly dividing NPCs. In contrast to the oscillatory expression of the Notch effectors Hes1 and Hes5 in fast cycling progenitors, Hey1 displays a non-oscillatory stationary expression pattern and contributes to the long-term maintenance of NSCs. These findings reveal a novel division of labor in Notch effectors where cell cycle rate biases effector selection and cell fate.

scholarly journals IL2 Neural stem cell regulation and brain development

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Yukiko Gotoh
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Underlying Mechanism ◽  
Ependymal Cells ◽  
Stem Cell Regulation ◽  
Cycle Arrest ◽  
Adult Nscs ◽  
Neural Stem Progenitor Cells ◽  
The Brain

Abstract Quiescent neural stem cells (NSCs) in the adult mouse brain are the source of neurogenesis that regulates innate and adaptive behaviors. Adult NSCs in the subventricular zone (SVZ) are derived from a subpopulation of embryonic neural stem-progenitor cells (NPCs) that is characterized by a slower cell cycle relative to the more abundant rapid cycling NPCs that build the brain. We have previously shown that slow cell cycle can cause the establishment of adult NSCs at the SVZ, although the underlying mechanism remains unknown. We found that Notch and an effector Hey1 form a module that is upregulated by cell cycle arrest in slowly dividing NPCs. In contrast to the oscillatory expression of the Notch effectors Hes1 and Hes5 in fast cycling progenitors, Hey1 displays a non-oscillatory stationary expression pattern and contributes to the long-term maintenance of NSCs. These findings reveal a novel division of labor in Notch effectors where cell cycle rate biases effector selection and cell fate. I will also discuss the heterogeneity of slowly dividing embryonic NPCs and the lineage relationship between adult NSCs and ependymal cells, which together form the niche for adult neurogenesis at the SVZ.

scholarly journals Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression

2015 ◽  
Vol 35 (2) ◽  
pp. 162-174 ◽  
Author(s):  
David Q. Matus ◽  
Lauren L. Lohmer ◽  
Laura C. Kelley ◽  
Adam J. Schindler ◽  
Abraham Q. Kohrman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Histone Deacetylase ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Invasive Cell

scholarly journals FLIP(L) determines p53 induced life or death

2019 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Fiammetta Falcone ◽  
Nyree T. Crawford ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Hdac Inhibitors ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
P53 Target Genes ◽  
Mdm2 Inhibitor

AbstractHow p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.

scholarly journals Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro

Oncotarget ◽  
2015 ◽  
Vol 6 (35) ◽  
pp. 37083-37097 ◽  
Author(s):  
Giulia Zanni ◽  
Elena Di Martino ◽  
Anna Omelyanenko ◽  
Michael Andäng ◽  
Ulla Delle ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Progenitor Cells ◽  
Cycle Arrest ◽  
Neural Stem Progenitor Cells

scholarly journals MYC Abrogates p53-Mediated Cell Cycle Arrest in N-(Phosphonacetyl)-l-Aspartate-Treated Cells, Permitting CAD Gene Amplification

1998 ◽  
Vol 18 (1) ◽  
pp. 536-545 ◽  
Author(s):  
Olga B. Chernova ◽  
Michail V. Chernov ◽  
Yukihito Ishizaka ◽  
Munna L. Agarwal ◽  
George R. Stark
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Gene Amplification ◽  
Dna Breaks ◽  
Pyrimidine Nucleotides ◽  
Cycle Arrest ◽  
Dependent Cell ◽  
Cad Gene ◽  
Resistant Cells

ABSTRACT Genomic instability, including the ability to undergo gene amplification, is a hallmark of neoplastic cells. Similar to normal cells, “nonpermissive” REF52 cells do not develop resistance toN-(phosphonacetyl)-l-aspartate (PALA), an inhibitor of the synthesis of pyrimidine nucleotides, through amplification of cad, the target gene, but instead undergo protective, long-term, p53-dependent cell cycle arrest. Expression of exogenous MYC prevents this arrest and allows REF52 cells to proceed to mitosis when pyrimidine nucleotides are limiting. This results in DNA breaks, leading to cell death and, rarely, to cad gene amplification and PALA resistance. Pretreatment of REF52 cells with a low concentration of PALA, which slows DNA replication but does not trigger cell cycle arrest, followed by exposure to a high, selective concentration of PALA, promotes the formation of PALA-resistant cells in which the physically linked cad and endogenous N-myc genes are coamplified. The activated expression of endogenous N-myc in these pretreated PALA-resistant cells allows them to bypass the p53-mediated arrest that is characteristic of untreated REF52 cells. Our data demonstrate that two distinct events are required to form PALA-resistant REF52 cells: amplification ofcad, whose product overcomes the action of the drug, and increased expression of N-myc, whose product overcomes the PALA-induced cell cycle block. These paired events occur at a detectable frequency only when the genes are physically linked, ascad and N-myc are. In untreated REF52 cells overexpressing N-MYC, the level of p53 is significantly elevated but there is no induction of p21 waf1 expression or growth arrest. However, after DNA is damaged, the activated p53 executes rapid apoptosis in these REF52/N-myc cells instead of the long-term protective arrest seen in REF52 cells. The predominantly cytoplasmic localization of stabilized p53 in REF52/N-myc cells suggests that cytoplasmic retention may help to inactivate the growth-suppressing function of p53.

scholarly journals Id2Reverses Cell Cycle Arrest Induced by γ-Irradiation in Human HaCaT Keratinocytes

2005 ◽  
Vol 280 (16) ◽  
pp. 15836-15841 ◽  
Author(s):  
Sandrine Baghdoyan ◽  
Jérôme Lamartine ◽  
David Castel ◽  
Amandine Pitaval ◽  
Yoann Roupioz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Ionizing Radiation ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Physiological Role ◽  
Human Keratinocytes ◽  
Γ Irradiation ◽  
Cycle Arrest ◽  
Radiation Induced ◽  
The Impact

Id2 plays a key role in epithelial cells, regulating differentiation, the cell cycle, and proliferation. Because human skin constantly renews itself and is the first target of irradiation, it is of primary interest to evaluate whether such a gene may be regulated in keratinocytes exposed to ionizing radiation. We show here thatId2is induced in response to γ-irradiation and have investigated the consequence of this regulation on cell fate. Using RNA interference, we observed that Id2 extinction significantly reduces cell growth in human keratinocytes through the control of the G1-S transition of the cell cycle. We have investigated whether the impact of Id2 on the cell cycle may have a physiological role on the cell's ability to cope with radiative stress. Indeed, when Id2 is down-regulated through interfering RNA, cells are more sensitive to irradiation. Conversely, when Id2 is overexpressed, this somehow protects the cell. We propose that Id2 favors reentering the cell cycle after radiation-induced cell cycle arrest to permit the recovery of keratinocytes exposed to ionizing radiation.

scholarly journals Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marina Farkas ◽  
Hideharu Hashimoto ◽  
Yingtao Bi ◽  
Ramana V. Davuluri ◽  
Lois Resnick-Silverman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Binding Modes ◽  
Cell Fate Decisions ◽  
Cycle Arrest

AbstractThe tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the code are embedded in the DNA shape. We further demonstrate that differences in minor/major groove widths, encoded by G/C or A/T bp content at positions 3, 8, 13, and 18 in the RE, determine distinct p53 DNA-binding modes by inducing different Arg248 and Lys120 conformations and interactions. The predictive capacity of this code was confirmed in vivo using genome editing at the BAX RE to interconvert the DNA-binding modes, transcription pattern, and cell fate outcome.

scholarly journals The pseudo-caspase FLIP(L) regulates cell fate following p53 activation

2020 ◽  
Vol 117 (30) ◽  
pp. 17808-17819 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Nyree T. Crawford ◽  
Fiammetta Falcone ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
Induced Apoptosis

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

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