Regulation of the Cellular Prion Protein Gene Expression Depends on Chromatin Conformation

Cabral, Ana Lucia Beirão; Lee, Kil Sun; Martins, Vilma R.

doi:10.1074/jbc.m104815200

Cited by 24 publications

(18 citation statements)

References 60 publications

(56 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 99%

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Rat PC12 pheochromocytoma and C6 glioma clones stably transfected with a luciferase reporter vector driven by the rat Prnp promoter region (Ϫ2,831 to ϩ47 bp) (52) have been previously described (10). PC12 cells were routinely grown in RPMI medium (Sigma) supplemented with 10% HS, 5% fetal bovine serum (FBS; GIBCO), 100 U/ml penicillin and 100 g/ml streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…To assess the stimulatory effect of copper on the rat Prnp promoter activity, PC12 and C6 clones stably transfected with a luciferase reporter vector driven by the rat Prnp promoter were used (10). Three different clones of each cell line were treated with 100 M CuCl 2 for 16 h. As shown in Fig.…”

Section: Copper Induces the Expression Of Prp C In Cultured Rat Neuronsmentioning

confidence: 99%

Induction of cellular prion protein gene expression by copper in neurons

Varela-Nallar¹,

Toledo²,

Larrondo³

et al. 2006

American Journal of Physiology-Cell Physiology

Self Cite

View full text Add to dashboard Cite

Prion diseases are caused by the conformational transition of the native alpha-helical cellular prion protein (PrPC) into a beta-sheet pathogenic isoform. However, the normal physiological function of PrPC remains elusive. We report herein that copper induces PrPC expression in primary hippocampal and cortical neurons. PrPC induced by copper has a normal glycosylation pattern, is proteinase K-sensitive and reaches the cell surface attached by a glycosyl phosphatidylinositol anchor. Immunofluorescence analysis revealed that copper induces PrPC levels in the cell surface and in an intracellular compartment that we identified as the Golgi complex. In addition, copper induced the activity of a reporter vector driven by the rat PrPC gene (Prnp) promoter stably transfected into PC12 cells, whereas no effect was observed in glial C6 clones. Also cadmium, but not zinc or manganese, upregulated Prnp promoter activity in PC12 clones. Progressive deletions of the promoter revealed that the region essential for copper modulation contains a putative metal responsive element. Although electrophoretic mobility shift assay demonstrated nuclear protein binding to this element, supershift analysis showed that this is not a binding site for the metal responsive transcription factor-1 (MTF-1). The MTF-1-independent transcriptional activation of Prnp is supported by the lack of Prnp promoter activation by zinc. These findings demonstrate that Prnp expression is upregulated by copper in neuronal cells by an MTF-1-independent mechanism, and suggest a metal-specific modulation of Prnp in neurons.

show abstract

“…The murine Abca1 gene possesses a strong cAMP responsive element (CRE) in its first intron and expression of Abca1 can be enhanced by cAMP analogues (Le Goff et al, 2006). The Prnp gene lacks consensus CRE sites and PrP mRNA levels are not increased by cAMP analogue treatment (Cabral et al, 2002). cAMP analogues have often been used to induce ABCA1 expression for studying its role in cholesterol transport (Lawn et al, 1999;Le Goff et al, 2006) and are used here to induce endogenous ABCA1 expression and study its impact on the concentration of PrP C or PrP Sc .…”

Section: Increased Expression Of Abca1 Elevates Prp C and Prp Sc Levelsmentioning

confidence: 99%

Cholesterol transporter ATP-binding cassette A1 (ABCA1) is elevated in prion disease and affects PrPC and PrPSc concentrations in cultured cells

Kumar

McClain

Young

et al. 2008

Journal of General Virology

View full text Add to dashboard Cite

Prion diseases are transmissible neurodegenerative disorders of prion protein (PrP) conformation. Prion replication by conversion of benign PrP C isoforms into disease-specific PrP Sc isoforms is intimately involved in prion disease pathogenesis and may be initiated in cholesterol-rich caveolae-like domains (CLD). Concentrations of the cholesterol transporter ATP-binding cassette A1 protein (ABCA1) are elevated in pre-clinical scrapie prion-infected mice and in prion-infected cells in vitro. Elevation of ABCA1 in prion-infected brain is not a direct consequence of local PrP Sc accumulation, indeed levels of ABCA1 are comparable in brain regions that differ dramatically in the amount of PrP Sc . Similarly, ABCA1 concentrations are identical in normal mice, transgenic mice overexpressing PrP and PrP knockout mice. In contrast, PrP C and PrP Sc levels, but not Prnp mRNA, were increased by overexpression of ABCA1 in N2a neuroblastoma cells and scrapie prion-infected N2a cells (ScN2a). Conversely, RNAi-mediated knock down of Abca1 expression decreased the concentrations of PrP C in N2a cells and of PrP Sc in ScN2a cells. These results suggest that ABCA1's effects on PrP C levels are post-translational and may reflect an increase in of PrP C stability, mediated either indirectly by increasing membrane cholesterol and CLD formation or by other functions of ABCA1. The increased supply of PrP C available for conversion would lead to increased PrP Sc formation. INTRODUCTIONCreutzfeldt-Jakob disease and Kuru in humans, bovine spongiform encephalopathy, scrapie in sheep and chronic wasting disease in cervids are members of the group of neurodegenerative protein folding disorders caused by prions (Prusiner, 1998). Prion replication involves conversion of benign cellular isoforms, designated PrP C , into disease-specific isoforms, designated PrP Sc . The cellular site for prion replication is not well defined; in vitro and in vivo studies suggest that it takes place at the plasma membrane, where the initial interaction between endogenous glycosylphosphatidylinositol (GPI)-anchored PrP C and exogenous PrP Sc occurs, and in endosomal compartments (Campana et al., 2005;Harris, 1999). Substantial evidence suggests that PrP Sc generation takes place in cholesterol-rich, detergent insoluble membrane domains that are identified by various names, including caveolae-like domains (CLD), detergent resistant membranes and lipid rafts (Caughey & Raymond, 1991;Kaneko et al., 1997; Sarnataro et al., 2004;Vey et al., 1996). Cholesterol is required for PrP C cellsurface expression and stability (Caughey & Raymond, 1991;Gilch et al., 2006;Kaneko et al., 1997; Sarnataro et al., 2004) and pharmacological treatments that lower cellular cholesterol reduce PrP Sc generation and prolong prion incubation time (Bate et al., 2004;Gilch et al., 2006;Marella et al., 2002; Taraboulos et al., 1995).Genes involved in cholesterol metabolism and transport are consistently found among differentially expressed genes (DEGs) in prion-infected mice and cell line...

show abstract

Regulation of the Cellular Prion Protein Gene Expression Depends on Chromatin Conformation

Cited by 24 publications

References 60 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

Induction of cellular prion protein gene expression by copper in neurons

Cholesterol transporter ATP-binding cassette A1 (ABCA1) is elevated in prion disease and affects PrPC and PrPSc concentrations in cultured cells

Contact Info

Product

Resources

About