p53‐Mediated Activities in <scp>NS</scp>‐5 Neural Stem Cells: Effects of Ethanol

Miller, Michael W.

doi:10.1111/acer.13976

Cited by 5 publications

(3 citation statements)

References 85 publications

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“…Alcohol’s induction of nucleolar stress offers insight into its known ability to induce p53 in diverse neural lineages, including those derived from the cortex [ 45 ], somatosensory cortex [ 25 ], dorsal root ganglia [ 46 ], and immortalized NSCs [ 43 , 47 ], as well as cranial neural crest cells [ 23 , 24 , 48 ]. This is accompanied by the up-regulation of p53-dependent pathways [ 21 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain

Huang,

Flentke,

Rivera

et al. 2024

Cells

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Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5–E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (Polr1d, Rpl11; Rpl35; Nhp2); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol’s actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage.

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Section: Discussionmentioning

confidence: 99%

Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain

Huang,

Flentke,

Rivera

et al. 2024

Cells

View full text Add to dashboard Cite

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“…Previous reports have shown that EtOH causes DNA damage and increases p53. (33) Since p53 is known to enhance transcription of DUSP6, (34) the p53-DUSP6 pathway may be involved in EtOH induced DUSP6 expression. However, DUSP6 expression is reduced in the cerebral cortex of rats exposed to EtOH vapor for 7 weeks.…”

Section: Discussionmentioning

confidence: 99%

Ethanol enhances selenoprotein P expression via ERK-FoxO3a axis in HepG2 cells

Chen,

Mita,

Noguchi

2024

J. Clin. Biochem. Nutr.

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Drinking alcohol is considered one of the risk factors for development of diabetes mellitus.Recently, it was reported that selenoprotein P (SeP) levels in blood are increased by ethanol intake. However, the mechanism by which ethanol increases SeP has not been elucidated. The expression ofSeP protein and its mRNA were increased in a concentration-and timedependent manner when human liver-derived HepG2 cells were treated with ethanol. Levels of AMPK and JNK proteins, which have been known to regulate SeP transcription, were unchanged by ethanol treatment. However, the amount of nuclear FoxO3a, a transcription factor of SeP, was increased. This was associated with dephosphorylation of ERK1 but not ERK2. It was found that ERK1 was dephosphorylated by activation of dual-specific phosphatase 5 (DUSP5) and DUSP6. However, the phosphorylation of MEK by ERK phosphokinase was not affected by ethanol treatment. These results suggest that the ethanol-induced increase in SeP levels occurs by enhanced transcription of SeP mRNA via the DUSP5/6-ERK1-FoxO3a pathway.

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“…The above effect was more obvious for NSCs treated with TGFβ‐1 (Hicks & Miller, 2019). Similarly, another study revealed that ethanol and TGFβ‐1 induced changes in the number of proliferating NSCs were significantly enhanced after NSCs treatment with p53 siRNA (Miller, 2019). The experiment illustrated the synergistic actions of TGFβ‐1 and ethanol in inducing DNA damage and triggering DDR.…”

Section: Nscs Regulate Factors Related To Dna Damage Repairmentioning

confidence: 91%

The role of DNA damage in neural stem cells ageing

Zhong,

Wang,

Yang

et al. 2024

Journal Cellular Physiology

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Neural stem cells (NSCs) are pluripotent stem cells with the potential to differentiate into a variety of nerve cells. NSCs are susceptible to both intracellular and extracellular insults, thus causing DNA damage. Extracellular insults include ultraviolet, ionizing radiation, base analogs, modifiers, alkyl agents and others, while intracellular factors include Reactive oxygen species (ROS) radicals produced by mitochondria, mismatches that occur during DNA replication, deamination of bases, loss of bases, and more. When encountered with DNA damage, cells typically employ three coping strategies: DNA repair, damage tolerance, and apoptosis. NSCs, like many other stem cells, have the ability to divide, differentiate, and repair DNA damage to prevent mutations from being passed down to the next generation. However, when DNA damage accumulates over time, it will lead to a series of alterations in the metabolism of cells, which will cause cellular ageing. The ageing and exhaustion of neural stem cell will have serious effects on the body, such as neurodegenerative diseases. The purpose of this review is to examine the processes by which DNA damage leads to NSCs ageing and the mechanisms of DNA repair in NSCs.

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p53‐Mediated Activities in NS‐5 Neural Stem Cells: Effects of Ethanol

Cited by 5 publications

References 85 publications

Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain

Alcohol Exposure Induces Nucleolar Stress and Apoptosis in Mouse Neural Stem Cells and Late-Term Fetal Brain

Ethanol enhances selenoprotein P expression via ERK-FoxO3a axis in HepG2 cells

The role of DNA damage in neural stem cells ageing

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