Inhibition of basal activity of c-jun-NH2-terminal kinase (JNK) represses the expression of presenilin-1 by a p53-dependent mechanism

Presenilin-1 (PS1) is a multifunctional protein involved in many cellular functions including the processing of type 1 transmembrane proteins and regulation of calcium signaling. Although PS1 is important in many aspects of cellular functions, little is known about the PS1 gene regulation in the context of intracellular signal pathways. We tested the role of c-jun-NH2-terminal kinase (JNK) on PS1 gene expression using a JNK specific inhibitor, SP600125. SP600125 efficiently suppressed basal JNK activity in SK-N-SH cell line as shown by inhibition of phosphor-JNK and phosphor-c-jun, and also decreased PS1 expression. Previously we reported that Ets1/2 bind to the PS1 promoter to activate PS1 transcription and p53 represses PS1 transcription without direct binding to the PS1 promoter [Pastorcic, M., Das, H.K., 2000. Regulation of transcription of the human presenilin-1 gene by ets transcription factors and the p53 protooncogene. J Biol Chem. 275, 34938–45.]. Involvement of protein–protein interaction between p53 and other transcription factors was speculated to be a mechanism by which p53 represses PS1 expression. Therefore, we tested whether the interaction between p53 and Ets1/2 is involved in JNK-mediated inhibition of PS1 expression. In this report we showed that p53 level was upregulated by SP600125 in SK-N-SH cell line. In addition, protein–protein interaction between p53 and Ets1/2 was enhanced with a concomitant dissociation of Ets1/2 from the PS1 promoter resulting in the suppression of PS1 transcription. We also showed that suppression of JNK1 by JNK1 siRNA increased p53 protein level and decreased PS1 expression. This observation was supported by the fact that overexpression of p53 in SK-N-SH cell line promoted dissociation of Ets1/2 from the PS1 promoter and suppressed PS1 expression. Furthermore, p53 inhibitor pifithrin-α partially nullified the suppressive effects of SP600125 on PS1 expression. We also showed that transfection of p53 was required for SP600125-mediated suppression of PS1 expression in p53-deficient PC3 cell line suggesting that inhibition of basal JNK activity suppresses PS1 expression through a p53-dependent mechanism.