The nucleic acid binding protein, Pur-alpha, is best characterized as a transcription factor with affinity to single stranded G/C rich regions. Pur-alpha exhibits developmental and tissue-specific regulation and plays a critical role in neuronal development and differentiation. Similar to Pur-alpha, the amyloid-β protein precursor (AβPP) is a developmentally regulated protein which promotes neuronal survival. Both the human and mouse AβPP promoters contain multiple G/C rich sequences which regulate AβPP at the transcriptional and translational levels. Using an in vitro reporter assay, we confirmed that Pur-alpha consensus binding sites within the human AβPP promoter down-regulate AβPP transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays (ChIP) showed direct binding of Pur-alpha to the AβPP promoter. Down regulation of AβPP went beyond the transcriptional level as overexpression of Pur-alpha in glial and fibroblast cell lines decreased basal levels of AβPP while siRNA targeting Pur-alpha increased basal levels of AβPP. Similar findings were observed in brain tissue and fibroblasts from mice with targeted deletion of Pur-alpha. These data point to a novel mechanism of controlling AβPP levels by the transcriptional regulatory protein, Pur-alpha, and suggest that Pur-alpha may be involved in the dysregulation of AβPP in Alzheimer’s disease.

Negative Regulation of AβPP GeneExpression by Pur-alpha

BASILE, ANNA;
2008-01-01

Abstract

The nucleic acid binding protein, Pur-alpha, is best characterized as a transcription factor with affinity to single stranded G/C rich regions. Pur-alpha exhibits developmental and tissue-specific regulation and plays a critical role in neuronal development and differentiation. Similar to Pur-alpha, the amyloid-β protein precursor (AβPP) is a developmentally regulated protein which promotes neuronal survival. Both the human and mouse AβPP promoters contain multiple G/C rich sequences which regulate AβPP at the transcriptional and translational levels. Using an in vitro reporter assay, we confirmed that Pur-alpha consensus binding sites within the human AβPP promoter down-regulate AβPP transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays (ChIP) showed direct binding of Pur-alpha to the AβPP promoter. Down regulation of AβPP went beyond the transcriptional level as overexpression of Pur-alpha in glial and fibroblast cell lines decreased basal levels of AβPP while siRNA targeting Pur-alpha increased basal levels of AβPP. Similar findings were observed in brain tissue and fibroblasts from mice with targeted deletion of Pur-alpha. These data point to a novel mechanism of controlling AβPP levels by the transcriptional regulatory protein, Pur-alpha, and suggest that Pur-alpha may be involved in the dysregulation of AβPP in Alzheimer’s disease.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/3244077
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact