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

Cooperation between GATA4 and TGF-β signaling regulates intestinal epithelial gene expression

“…Such Sp1 sites are not readily discernible in the Ϫ306 IFABP promoter. Sp1 has been shown to recruit Smad2/3/4 and mediate activation of TGF-␤ target genes such as p15 (Ink4B), plasminogen activator inhibitor 1, collagen alpha 2(I) and amyloid beta precursor protein (18,24,30,68).…”

TGF‐β1/SMAD signaling induces astrocyte fate commitment in vitro: Implications for radial glia development

“…Following TGF-b receptor activation, the cytosolic receptor-regulated Smads 2 and 3 are phosphorylated and associate with the common-partner Smad 4 forming heteromeric complexes, which translocate to the nucleus to modulate TGF-b-target genes (Shi and Massagu e, 2003). In the CNS there is scarce evidence of Smad pathway in astrocytes (Burton et al, 2002;Docagne et al, 2002;K€ onig et al, 2005), most of them, indirect, provided by transfection assays using Smad constructs (Docagne et al, 2002(Docagne et al, , 2004.…”

“…TGF-b1 has been reported to modulate the expression of several astrocytic genes including the cyclin-dependent kinase inhibitor p15 (Rich et al, 1999), amyloid precursor protein (Burton et al, 2002;Docagne et al, 2004), plasminogen activator inhibitor-1 (Docagne et al, 2002), and GFAP (de Sampaio e Spohr et al, 2002;Laping et al, 1994;Reilly et al, 1998;Sakai et al, 1990;Sousa et al, 2004). The molecular mechanism whereby TGF-b1 induces transcription of these genes is not completely elucidated yet.…”

“…Although TGF-b responsive domains have not been identified within the GFAP gene promoter, cooperation between Smad proteins and other molecules might mediate Smad-GFAP gene promoter interaction (Blokzijl et al, 2003;Kamakura et al, 2004;Nakashima et al, 1999;Rajan et al, 2003). Previous studies underlying the intracellular TGF-b/Smad pathway in astrocytes demonstrated that the ultimate intensity of TGF-b signaling is tightly modulated by nuclear Smad binding partners, which interact with Smads controlling their availability (Docagne et al, 2004;Shi and Massagu e, 2003). Supporting this idea, formation of a complex between STAT3 and Smad 1 has been involved in the activation of GFAP gene of neural progenitors in response to LIF and BMP2 (Li and Grumet, 2007;Nakashima et al, 1999), probably by binding to STAT binding sites.…”

The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons

“…Though the increased levels of TGFβ1 in AD [215,216] does not seem to be able to compensate for the compromised canonical neuronal Smad pathway [148,190], astrocytes were shown responsive to this growth factor, which induces amyloid precursor protein (APP) expression in cooperation with Sp1 [217] and CTCF [218]. Altered APP cleavage by the concerted action of α-, β-and γ-secretases is a main aspect of AD pathology and results in the generation of the pathogenetic βA4 peptide 1-42, which is neurotoxic and leads to βA4-amyloid plaques.…”