p53 directly regulates the transcription of the human frataxin gene and its lack of regulation in tumor cells decreases the utilization of mitochondrial iron

Shimizu, Rina; Lan, Nguyễn Ngọc; Tai, Tran Tien; Adachi, Yuka; Kawazoe, Asako; Mu, Anfeng; Taketani, Shigeru

doi:10.1016/j.gene.2014.08.043

Cited by 28 publications

(20 citation statements)

References 29 publications

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“…37,38 G-CSF and SCF had pronounced effects on frataxin levels and on regulators of frataxin expression within both the cerebellum and spinal cord. Of the potential transcription factors we tested, [31][32][33] HIF-2alpha encoded by Epas1 was upregulated in the cerebellum and spinal cord in response to treatment and correlated with FXN expression, highlighting a possible regulatory mechanism by which G-CSF and SCF control frataxin expression. Indeed, others have shown that HIF-2alpha can activate the murine FXN promoter through binding to a consensus HIF-responsive enhancer element, and mice lacking Epas1 have markedly reduced levels of frataxin.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, in all cases, increases in frataxin mRNA expression were more prominent using the neuronal-specific marker, NeuN, housekeeping gene comparator, suggesting that the treatments, at least in part, potentiate increases in neuronal frataxin. Transcriptional repression of FXN is thought to result from reduced accessibility of transcriptional regulatory factors to the promoter region caused by the trinucleotide repeat expansion, 30 and various regulatory factors binding close to the FXN gene locus are implicated [31][32][33] (Fig 4A). Of these, we found that tumor protein p53 (p53; encoded by Trp53), transcription factor AP-2 alpha (TFAP2A; encoded by Tfap2a), serum response factor (SRF; encoded by Srf ), and hypoxia-inducible factor-2alpha (HIF-2A; encoded by Epas1) were increased following cytokine administration ( Fig 4C).…”

Section: G-csf and Scf Increase Frataxin Messenger Rna And Protein Exmentioning

confidence: 99%

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Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

Kemp

Cerminara

Hares

et al. 2017

Annals of Neurology

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ObjectivesFriedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte‐colony stimulating factor (G‐CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia.MethodsMice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum.ResultsCytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G‐CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine‐induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease‐related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury.InterpretationThese experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease‐modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212–226

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Section: Discussionmentioning

confidence: 99%

Section: G-csf and Scf Increase Frataxin Messenger Rna And Protein Exmentioning

confidence: 99%

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

Kemp

Cerminara

Hares

et al. 2017

Annals of Neurology

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“…Further supporting frataxin in the role of tumor suppressor is the fact that p53 has been shown to decrease the level of frataxin mRNA in human kidney HEK293T cells and that the human frataxin gene proximal promoter contains a p53-responsive element (p53RE), which is involved in p53-mediated control of frataxin expression. 33 Evidence provided by a yeast model of FRDA also suggests that increased levels of DNA damage occurs in FRDA and the absence of frataxin leads to nuclear damage, chromosomal instability and a greater sensitivity to DNA-damaging agents. 34 In a study on FRDA peripheral blood mononuclear cells, increased mitochondrial and nuclear DNA damage also results in changes in gene expression indicative of genotoxicity stress.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

et al. 2016

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Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by deficiency of frataxin protein, with the primary sites of pathology being the large sensory neurons of the dorsal root ganglia and the cerebellum. FRDA is also often accompanied by severe cardiomyopathy and diabetes mellitus. Frataxin is important in mitochondrial iron–sulfur cluster (ISC) biogenesis and low-frataxin expression is due to a GAA repeat expansion in intron 1 of the FXN gene. FRDA cells are genomically unstable, with increased levels of reactive oxygen species and sensitivity to oxidative stress. Here we report the identification of elevated levels of DNA double strand breaks (DSBs) in FRDA patient and YG8sR FRDA mouse model fibroblasts compared to normal fibroblasts. Using lentivirus FXN gene delivery to FRDA patient and YG8sR cells, we obtained long-term overexpression of FXN mRNA and frataxin protein levels with reduced DSB levels towards normal. Furthermore, γ-irradiation of FRDA patient and YG8sR cells revealed impaired DSB repair that was recovered on FXN gene transfer. This suggests that frataxin may be involved in DSB repair, either directly by an unknown mechanism, or indirectly via ISC biogenesis for DNA repair enzymes, which may be essential for the prevention of neurodegeneration.

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“…This differential modulation of p53 activation by Fxn expression level in normoxia and hypoxia might also lead to a differential recruitment of distinct p53 downstream targets (Guccini et al, 2011). On the other hand, it has been recently described that p53 activates the transcription of the FXN gene in a human embryonic kidney cell line (Shimizu et al, 2014). Further research is necessary to clarify the complex interrelationship between Fxn and p53 in distinct cell types under different physiopathological conditions.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

Loría

Díaz‐Nido

2015

Neurobiology of Disease

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Friedreich's ataxia (FA) is a recessive, predominantly neurodegenerative disorder caused in most cases by mutations in the first intron of the frataxin (FXN) gene. This mutation drives the expansion of a homozygous GAA repeat that results in decreased levels of FXN transcription and frataxin protein. Frataxin (Fxn) is a ubiquitous mitochondrial protein involved in iron-sulfur cluster biogenesis, and a decrease in the levels of this protein is responsible for the symptoms observed in the disease. Although the pathological manifestations of FA are mainly observed in neurons of both the central and peripheral nervous system, it is not clear if changes in non-neuronal cells may also contribute to the pathogenesis of FA, as recently suggested for other neurodegenerative disorders. Therefore, the aims of this study were to generate and characterize a cell model of Fxn deficiency in human astrocytes (HAs) and to evaluate the possible involvement of non-cell autonomous processes in FA. To knockdown frataxin in vitro, we transduced HAs with a specific shRNA lentivirus (shRNA37), which produced a decrease in both frataxin mRNA and protein expression, along with mitochondrial superoxide production, and signs of p53-mediated cell cycle arrest and apoptotic cell death. To test for non-cell autonomous interactions we cultured wild-type mouse neurons in the presence of frataxin-deficient astrocyte conditioned medium, which provoked a delay in the maturation of these neurons, a decrease in neurite length and enhanced cell death. Our findings confirm a detrimental effect of frataxin silencing, not only for astrocytes, but also for neuron-glia interactions, underlining the need to take into account the role of non-cell autonomous processes in FA.

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p53 directly regulates the transcription of the human frataxin gene and its lack of regulation in tumor cells decreases the utilization of mitochondrial iron

Cited by 28 publications

References 29 publications

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

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