Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription

Fabian Docagne, Cecilia Gabriel, Nathalie Lebeurrier, Sylvain Lesné, Yannick Hommet, Laurent Plawinski, Eric T. Mackenzie, Denis Vivien

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Abnormal deposition of Aβ (amyloid-β peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-β precursor protein). We have demonstrated previously that TGF-β (transforming growth factor-β), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Aβ. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-β-dependent transcriptional activity. We report the following findings: first, TGF-β is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the + 54/ + 74 region of the APP promoter, named APPTRE (APP TGF-β-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APPTRE. We also observed that the APPTRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-β-dependent activation of APP. TGF-β signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-β-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-β in the regulation of Aβ production.

Original languageEnglish (US)
Pages (from-to)393-399
Number of pages7
JournalBiochemical Journal
Volume383
Issue number2
DOIs
StatePublished - Oct 15 2004

Keywords

  • Alzheimer's disease
  • Cytokine
  • Luciferase
  • Promoter
  • Smad
  • Transforming growth factor-β

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