title: Sp1 and Smad transcription factors co-operate to mediate TGF-beta-dependent activation of amyloid-beta precursor protein gene transcription.
abstract: Abnormal deposition of Abeta (amyloid-beta 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-beta precursor protein). We have demonstrated previously that TGF-beta (transforming growth factor-beta), 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 Abeta. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-beta-dependent transcriptional activity. We report the following findings: first, TGF-beta is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APP(TRE) (APP TGF-beta-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 APP(TRE). We also observed that the APP(TRE) 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-beta-dependent activation of APP. TGF-beta 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-beta-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-beta in the regulation of Abeta production.
authors.affiliation: UMR CNRS 6185, Bd H. Becquerel, BP 5229, 14074 Caen Cedex, France. docagne@cajal.csic.es
authors.forename: Fabian
authors.initials: F
authors.lastname: Docagne
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gabriel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lebeurrier
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lesné
authors.forename: Yannick
authors.initials: Y
authors.lastname: Hommet
authors.forename: Laurent
authors.initials: L
authors.lastname: Plawinski
authors.forename: Eric T
authors.initials: ET
authors.lastname: Mackenzie
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008907:Mink; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins; D051900:Smad3 Protein; D051901:Smad4 Protein; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D051785:Smad Proteins; D051900:Smad3 Protein; D051901:Smad4 Protein; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051705:Sp3 Transcription Factor