Regulation of the cellular prion protein gene expression depends on chromatin conformation.
Conversion of the normal cellular prion protein (PrPc), whose physiological function is still under investigation, to an infectious form called prion is the cause of some neurodegenerative diseases. Therefore, the elucidation of PrPc gene regulation is important both to define a strategy to control the infection and to better understand PrPc function. We cloned the rat PrPc gene promoter region into a luciferase reporter vector, transfected C6 and PC-12 cells, and isolated clones with stable enzyme expression. The dependence of chromatin conformation on PrPc promoter activity was evaluated using the histone deacetylase inhibitor, trichostatin A, which was able to highly increase not only promoter activity but also PrPc mRNA and protein levels. The phorbol ester (12-O-tetradecanoylphorbol-13-acetate) and cAMP poorly induced promoter activity; retinoic acid decreased it by 50%, whereas nerve growth factor and dexamethasone had no effect. When 12-O-tetradecanoylphorbol-13-acetate or cAMP but not retinoic acid was associated with trichostatin A, a potentiation of the primary effects was observed. These new data indicate that PrPc gene regulation is highly dependent on disruption of chromatin fiber assembly, which allows some ubiquitous transcription factors accession to specific DNA elements.
Cabral
Ana Lucia B
AL
Ludwig Institute for Cancer Research, Departamento de Bioquimica, Instituto de Quimica da Universidade de São Paulo, Brazil.
Lee
Kil S
KS
Martins
Vilma R
VR
D000818:Animals; D015152:Blotting, Northern; D002843:Chromatin / Q000737:chemistry*; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D016716:PC12 Cells; D010703:Phorbol Esters; D018621:PrPC Proteins / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D013997:Time Factors; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
D002843:Chromatin; D006877:Hydroxamic Acids; D010703:Phorbol Esters; D018621:PrPC Proteins; C012589:trichostatin A; D014212:Tretinoin; D003907:Dexamethasone; D004247:DNA; D000242:Cyclic AMP; D008156:Luciferases