Activation and repression of prion protein expression by key regions of intron 1

Wright, Josephine; McHugh, Patrick; Stockbridge, Mark; Lane, Samantha; Kralovicova, Silvia; Brown, David R.

doi:10.1007/s00018-009-0154-8

Cited by 10 publications

(12 citation statements)

References 41 publications

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“…On the contrary, the down-regulation of PrP C expression has been observed in Cu-treated hypothalamic neurons (Toni et al 2005), meaning that the regulatory mechanisms depend on cell type. It is unlikely that cellspecific transcription factors are responsible for such variability, since those notoriously involved in P-rnp gene expression (Sp1, MTF-1, Ap-1, Ap-2, Atox-1) are ubiquitous (Bellingham et al 2009;Mahal et al 2001;Wright et al 2009). Based on previous epigenetic studies (Cabral et al 2002), a possible explanation could be that Cu deficiency acts in concert with unidentified cell-specific and ion-sensitive factors to disrupt the chromatin assembly and allow the accession of transcription factors to the P-rnp gene promoter.…”

Section: Discussionmentioning

confidence: 98%

Role of the Cellular Prion Protein in the Neuron Adaptation Strategy to Copper Deficiency

et al. 2012

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Copper transporter 1 (CTR1), cellular prion protein (PrP(C)), natural resistance-associated macrophage protein 2 (NRAMP2) and ATP7A proteins control the cell absorption and efflux of copper (Cu) ions in nervous tissues upon physiological conditions. Little is known about their regulation under reduced Cu availability, a condition underlying the onset of diffused neurodegenerative disorders. In this study, rat neuron-like cells were exposed to Cu starvation for 48 h. The activation of Caspase-3 enzymes and the impairment of Cu,Zn superoxide dismutase (Cu,Zn SOD) activity depicted the initiation of a pro-apoptotic program, preliminary to the appearance of the morphological signs of apoptosis. The transcriptional response related to Cu transport proteins has been investigated. Notably, PrP(C) transcript and protein levels were consistently elevated upon Cu deficiency. The CTR1 protein amount was stable, despite a two-fold increase in the transcript amount, meaning the activation of post-translational regulatory mechanisms. NRAMP2 and ATP7A expressions were unvaried. The up-regulated PrP(C) has been demonstrated to enhance the cell Cu uptake ability by about 50% with respect to the basal transport, and so sustain the Cu delivery to the Cu,Zn SOD cuproenzymes. Conclusively, the study suggests a pivotal role for PrP(C) in the cell adaptation to Cu limitation through a direct activity of ion uptake. In this view, the PrP(C) accumulation observed in several cancer cell lines could be interpreted as a molecular marker of cell Cu deficiency and a potential target of therapeutic interventions against disorders caused by metal imbalances.

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Section: Discussionmentioning

confidence: 98%

Role of the Cellular Prion Protein in the Neuron Adaptation Strategy to Copper Deficiency

et al. 2012

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“…For example, YY1 and Hes-1 have been identified as repressors [9], [10], whereas E4BP4, Atox-1, SP1, MTF-1, and HSTF-1 have been identified as activators [9], [10], [11], [12]. Furthermore, some exogenous and endogenous stimulating factors, such as thermal stimuli, Cu 2+ , hyperbaric oxygen, NO, IGF-1, and nerve growth factor (NGF), are believed to play a role in PRNP regulation [12], [13], [14], [15], [16], [17], [18].…”

Section: Introductionmentioning

confidence: 99%

IGF-1-Induced Enhancement of PRNP Expression Depends on the Negative Regulation of Transcription Factor FOXO3a

Liu

Feng

et al. 2013

PLoS ONE

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The conformational conversion of the cellular prion protein (PrPC) into its β-sheet-rich scrapie isoform (PrPSc) causes fatal prion diseases, which are also called transmissible spongiform encephalopathies (TSEs). Recent studies suggest that the expression of PrPC by the PRNP gene is crucial for the development of TSEs. Therefore, the identification of the exogenous and endogenous stimulating factors that regulate PRNP expression would help to understand the pathogenesis of TSEs. Here, we demonstrate that forkhead box O3a (FOXO3a) negatively regulates PRNP expression by binding to the PRNP promoter, which is negatively regulated by insulin-like growth factor 1 (IGF-1). Our results show that the IGF-1-induced enhancement of PRNP mRNA and protein levels is due to the activation of the PI3K-Akt signaling pathway. The activation of Akt then induces the phosphorylation of FOXO3a, leading to its translocation from the nucleus to the cytoplasm and preventing its binding to the PRNP promoter. Treatment with the PI3K-Akt inhibitor LY294002 induces the nuclear retention of FOXO3a, which leads to a decrease in PRNP expression. We present a new IGF-1-PI3K-Akt-FOXO3a pathway, which influences PRNP expression. The results of this work are vital for understanding the function of PrPC and for future therapeutic approaches to human TSEs.

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“…Although there are additional processes that can alter expression of prion protein (Wright et al 2009), in vitro studies have demonstrated prion protein expression to be modulated by the level of available copper in the medium (Toni et al 2005). In rats administered DEDC the levels of prion protein detected by western blot showed a biphasic response.…”

Section: Discussionmentioning

confidence: 99%

Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury

Valentine¹,

Viquez²,

Valentine³

2010

Toxicology

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Previous studies have demonstrated that N,N-diethyldithiocarbamate (DEDC) elevates copper and promotes oxidative stress within the nervous system. However, whether these effects resolve following cessation of exposure or have the potential to persist and result in cumulative injury has not been determined. In this study, an established model for DEDC myelin injury in the rat was used to determine whether copper levels, oxidative stress, and neuromuscular deficits resolve following the cessation of DEDC exposure. Rats were exposed to DEDC for 8 weeks and then either euthanized or maintained for 2, 6 or 12 weeks after cessation of exposure. At each time point copper levels were measured by inductively coupled mass spectrometry to assess the ability of sciatic nerve, brain, spinal cord and liver to eliminate excess copper post exposure. The protein expression levels of glutathione transferase alpha, heme oxygenase 1 and superoxide dismutase 1 in peripheral nerve and brain were also determined by western blot to assess levels of oxidative stress as a function of post exposure duration. As an initial assessment of the bioavailability of the excess copper in brain the protein expression levels of copper chaperone for superoxide dismutase 1, and prion protein were determined by western blot as a function of exposure and post exposure duration. Neuromuscular function in peripheral nerve was evaluated using grip strengths, nerve conduction velocities, and morphologic changes at the light microscope level. The data demonstrated that in peripheral nerve, copper levels and oxidative stress return to control levels within several weeks after cessation of exposure. Neuromuscular function also showed a trend towards pre-exposure values, although the resolution of myelin lesions was more delayed. In contrast, total copper and antioxidant enzyme levels remained significantly elevated in brain for longer post exposure periods. The persistence of effects observed in brain suggests that the central nervous system is more susceptible to long-term cumulative adverse effects from dithiocarbamates. Additionally, significant changes in expression levels of chaperone © 2010 Elsevier Ireland Ltd. All rights reserved. * Corresponding Author: Department of Pathology, C3320 MCN VUMC, Nashville, TN 37232-2561, bill.valentine@vanderbilt.edu, fax 615-343-9825, phone 615-343-5836. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare that there are no conflicts of interest. NIH Public Access Author ManuscriptToxicology. Author manuscript; available in PM...

show abstract

Activation and repression of prion protein expression by key regions of intron 1

Cited by 10 publications

References 41 publications

Role of the Cellular Prion Protein in the Neuron Adaptation Strategy to Copper Deficiency

Role of the Cellular Prion Protein in the Neuron Adaptation Strategy to Copper Deficiency

IGF-1-Induced Enhancement of PRNP Expression Depends on the Negative Regulation of Transcription Factor FOXO3a

Peripheral nerve and brain differ in their capacity to resolve N,N-diethyldithiocarbamate-mediated elevations in copper and oxidative injury

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