The p53 Family in Brain Disease

Agostini, Massimiliano; Melino, Gerry; Bernassola, Francesca

doi:10.1089/ars.2017.7302

Cited by 18 publications

(13 citation statements)

References 166 publications

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“…Future investigation might add a further step in the comprehension of such transcriptionl regulation; it might occur that specific repressors take part and help coordinate the repression of the downstream miR sequence upon ELF exposure. P73 and ΔNp73 for instance share the same regulatory sequences with p53 on many different gene promoters likely including miR-34 [76] and are specifically involved in gene transcription in brain where they control physiological and pathological pathways [77,78]. ΔNp73α in particular works as an antagonist of p53/p73 functions in growth suppression and/or apoptosis and might be involved in miR-34 inhibition in response to ELF.…”

Section: Discussionmentioning

confidence: 99%

Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells

et al. 2017

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The exposure to extremely low-frequency magnetic fields (ELF-MFs) has been associated to increased risk of neurodegenerative diseases, although the underlying molecular mechanisms are still undefined. Since epigenetic modulation has been recently encountered among the key events leading to neuronal degeneration, we here aimed at assessing if the control of gene expression mediated by miRNAs, namely miRs-34, has any roles in driving neuronal cell response to 50-Hz (1 mT) magnetic field in vitro. We demonstrate that ELF-MFs drive an early reduction of the expression level of miR-34b and miR-34c in SH-SY5Y human neuroblastoma cells, as well as in mouse primary cortical neurons, by affecting the transcription of the common pri-miR-34. This modulation is not p53 dependent, but attributable to the hyper-methylation of the CpG island mapping within the miR-34b/c promoter. Incubation with N-acetyl-l-cysteine or glutathione ethyl-ester fails to restore miR-34b/c expression, suggesting that miRs-34 are not responsive to ELF-MF-induced oxidative stress. By contrast, we show that miRs-34 control reactive oxygen species production and affect mitochondrial oxidative stress triggered by ELF-MFs, likely by modulating mitochondria-related miR-34 targets identified by in silico analysis. We finally demonstrate that ELF-MFs alter the expression of the α-synuclein, which is specifically stimulated upon ELF-MFs exposure via both direct miR-34 targeting and oxidative stress. Altogether, our data highlight the potential of the ELF-MFs to tune redox homeostasis and epigenetic control of gene expression in vitro and shed light on the possible mechanism(s) producing detrimental effects and predisposing neurons to degeneration.

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Section: Discussionmentioning

confidence: 99%

Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells

et al. 2017

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“…The present study found that maternal folic acid deficient increased apoptosis of neural cells both in hippocampus and cortex in rat offspring. Apoptosis is executed by some members of evolutionarily conserved members of the Bcl‐2 family, caspase family, and TP53 family (Matusica et al, 2016; Agostini et al, 2018). TP53 activates several apoptotic genes (Tembe et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Maternal folic acid deficiency stimulates neural cell apoptosis via miR‐34a associated with Bcl‐2 in the rat foetal brain

Zhou

et al. 2018

Intl J of Devlp Neuroscience

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Embryonic development is a critical period wherein brain neurons are generated and organized. Maternal dietary folate, a cofactor in one‐carbon metabolism, modulates neurogenesis and apoptosis in foetal brain neurons. We hypothesized that aberrant neuronal apoptosis may affect the development of the central nervous system during maternal folic acid deficiency, with evident effects because maternal folic acid deficiency modulates the microRNA‐34a associated with Bcl‐2 pathway during embryonic development. Four‐week‐old female Sprague‐Dawley rats were divided randomly into two groups (10 rats per group): a folate‐deficient diet group and a folate‐normal diet group. The diets were administered to the rats 60 d before mating, which was continued for the pregnant dams until parturition. Maternal folic acid deficiency increased neuronal apoptosis in the hippocampus and the cortex in the offspring. Furthermore, maternal folic acid deficiency increased the ratio of cleaved caspase‐3/caspase‐3, followed by an increase in caspase‐3 activity. Moreover, maternal folic acid deficiency downregulated Bcl‐2 and upregulated Bax, and this effect associate with maternal folic acid deficient increases expression of microRNA‐34a. Together, the present results indicate that maternal folic acid deficiency stimulates neuronal apoptosis via microRNA‐34a associated with Bcl‐2 signalling in rat offspring.

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“…Together with the frequent p53 mutations in cancer [ 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ], this signalling leads to associate their function to oncosuppression [ 123 , 124 , 125 , 126 ]. There is, however, strong in vivo and in vitro evidence that the family is also implicated in the regulation of the CNS functions [ 127 , 128 , 129 , 130 , 131 ]. Mechanistically, the p53-family proteins control NSCs survival, self-renewal and terminal differentiation via a complex transcriptional regulatory network by binding to specific DNA sequences to regulate the expression of coding- and non-coding genes.…”

Section: Transcriptional Regulation Of Adult Neurogenesismentioning

confidence: 99%

Regulation of Adult Neurogenesis in Mammalian Brain

Niklison-Chirou

Agostini

Amelio

et al. 2020

IJMS

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100

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Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors.

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The p53 Family in Brain Disease

Abstract: Understanding the molecular mechanism(s) underlying the function of the p53 family could improve our general knowledge of the pathogenesis of brain disorders and potentially pave the road for new therapeutic intervention. Antioxid. Redox Signal. 29, 1-14.

Cited by 18 publications

References 166 publications

Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells

Fifty-Hertz Magnetic Field Affects the Epigenetic Modulation of the miR-34b/c in Neuronal Cells

Maternal folic acid deficiency stimulates neural cell apoptosis via miR‐34a associated with Bcl‐2 in the rat foetal brain

Regulation of Adult Neurogenesis in Mammalian Brain

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