Transcriptional regulation of the presenilin-1 gene controls gamma-secretase activity

Abstract

Inhibition of basal JNK activity by JNK inhibitor SP600125 or JNK1siRNA repressed presenilin-1 (PS1) expression in SK-N-SH cells by augmenting the level of p53, a repressor of the PS1 gene (1). We now showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited gamma-secretase mediated processing of amyloid precursor protein (APP) resulting in the accumulation of C99 fragment and the reduction of secreted Abeta40 level without altering the expression of nicastrin (NCT). Co-treatment of cells with SP600125 and p53 inhibitor, pifithrin-alpha, partially nullified the suppressive effects of SP610025 on PS1 expression and secreted Abeta40 level. Suppression of JNK1 by JNK1siRNA also decreased Abeta40 level. Furthermore, overexpression of the repressors p53, ZNF237 and CHD3 of the PS1 gene also suppressed the processing of APP through repression of PS1 transcription by deacetylation of histone at the PS1 promoter. Transcriptional activator Ets2 increased PS1 protein and secreted Abeta40 levels without affecting the expression of NCT by activating PS1 transcription via hyper-acetylation of histone at the PS1 promoter. Therefore, regulation of PS1 transcription modulates gamma-secretase activity.

Intraperitoneal injection of JNK-specific inhibitor SP600125 inhibits the expression of presenilin-1 and Notch signaling in mouse brain without induction of apoptosis

“…Both p-JNK and p53 proteins were localized in the cytosol (Figure 3B). These in vivo data are in agreement with our published in vitro data in SK-N-SH cells (Lee and Das, 2010). …”

“…We have shown previously that regulation of PS1 transcription controls γ-secretase activity (Lee and Das, 2010). We have also ascertained the mechanism by which inhibition of PS1 transcription reduces γ-secretase activity in SK-N-SH cells (Lee and Das, 2008; Lee and Das, 2010).…”

“…We have shown previously that regulation of PS1 transcription controls γ-secretase activity (Lee and Das, 2010). We have also ascertained the mechanism by which inhibition of PS1 transcription reduces γ-secretase activity in SK-N-SH cells (Lee and Das, 2008; Lee and Das, 2010). We have shown that p53 downregulates PS1 transcription, PS1 protein expression, and PS1-mediated γ-secretase activity in vitro in SK-N-SH cells (Lee and Das, 2008; Lee and Das, 2010).…”

“…We have also ascertained the mechanism by which inhibition of PS1 transcription reduces γ-secretase activity in SK-N-SH cells (Lee and Das, 2008; Lee and Das, 2010). We have shown that p53 downregulates PS1 transcription, PS1 protein expression, and PS1-mediated γ-secretase activity in vitro in SK-N-SH cells (Lee and Das, 2008; Lee and Das, 2010). p53 does not bind to the PS1 promoter but inhibits PS1 transcription by protein-protein interaction with Ets1/Ets2 transcription factors resulting in the dissociation of Ets1/Ets2 from the PS1 promoter and repression of PS1 expression (Lee and Das, 2008; Pastorcic and Das, 2000).…”

“…NICD subsequently migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. We have previously shown that inhibition of basal activity of c- jun -NH2-terminal kinase (JNK) with JNK-specific inhibitor SP600125 represses the expression of PS1 and γ-secretase activity by increasing p53 level in SK-N-SH cell line in vitro (Lee and Das, 2008; Lee and Das, 2010). However, it is largely unknown whether PS1 can be effectively suppressed in vivo in adult mouse brains.…”