Transcriptional Regulation Of APH-1A And PEN-2, Two Key Components Of γ-secretase Complex

The intramembrane proteolytic cleavages of Alzheimer'sβ-amyloid precursor protein (APP) and signaling receptor Notch are mediated by the PS/γ-secretase complex, which comprises of presenilins (PS, including PS1 and PS2), nicastrin (NCT), APH-1 and PEN-2. Although the four components have been shown to coordinately regulate each other at the protein level, information regarding their transcriptional regulation is scarce. In the present study, we characterized upstream regions of the human PEN-2 and APH-1A genes and identified sequences critical for their promoter activity. Sequence analysis of these regions revealed several potential transcription factor binding sites. Site mutations and gel shift assays showed that CREB binds to PEN-2 promoter, whereas AP4 and HIF-1 bind to APH-1A promoter. Furthermore, activation of CREB by forskolin treatment dramatically promoted the expression of PEN-2 mRNA and protein, but not the expression of the other threeγ-secretase components. Activation of HIF-1 by nickel (chemical hypoxia) significantly promoted the expression of APH-1A mRNA and protein; whereas increased protein levels of PEN-2 and PS1 were only observed after chronic nickel treatment. Importantly, the levels of various proteolytic metabolites of APP were also altered by forskolin or nickel treatment. Together, our results demonstrate the differential transcriptional regulation of PEN-2 and APH-1A expression, and suggest additional physiological functions uniquely assigned to PEN-2 and APH-1A.