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

Presenilin-1 (PSI) is a multifunctional protein involved in many cellular functions including the processing of type 1 transmembrane proteins and regulation of calcium signaling. Although PSI is important in many aspects of cellular functions, little is known about the PSI gene regulation in the context of intracellular signal pathways. We tested the role of c-jun-NH2-terminal kinase (JNK) on PSI 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 PSI expression. Previously we reported that Ets1/2 bind to the PSI promoter to activate PSI transcription and p53 represses PSI transcription without direct binding to the PSI 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 PSI expression. Therefore, we tested whether the interaction between p53 and Ets1/2 is involved in JNK-mediated inhibition of PSI 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 PSI promoter resulting in the suppression of PSI transcription. We also showed that suppression of JNK1 by JNK1 siRNA increased p53 protein level and decreased PSI 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 PSI promoter and suppressed PSI expression. Furthermore, p53 inhibitor pifithrin-a partially nullified the suppressive effects of SP600125 on PSI expression. We also showed that transfection of p53 was required for SP600125-mediated suppression of PSI expression in p53-deficient PC3 cell line suggesting that inhibition of basal JNK activity suppresses PSI expression through a p53-dependent mechanism. (C) 2008 Elsevier B.V. All rights reserved.