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Figure 3. Schema of the features of the APH-1A promoter, and the hypoxia/HIF-1 regulated APH-1A expression and APP/Notch processing. The major transcription initiation site (TIS, numbered at +1) is at 211 bp upstream of the APH-1A protein coding sequence (CDS). Sequence prediction, mutagenesis, and gel shift assays showed that the APH-1A promoter possesses three AP4 binding sites and one HIF-1 binding site, which was predicted from bp + 103 to bp + 117. Nickel treatment (a condition of chemical hypoxia) or hypoxia increases HIF-1
concentration, which binds to HIF-1ß to form activated HIF-1 heterodimers. Activated HIF-1 promotes the transcription and translation of APH-1A. Increased APH-1A concentration probably promotes the 
-secretase activity, hence enhances the processing of APP to generate Aß and the cleavage of Notch to release NICD. Alternatively, it is possible that nickel/hypoxia changes the intracellular/intramembranous microenvironments or affects protein intracellular trafficking, rendering the substrates more susceptible to the -secretase. The dashed lines indicate hypothetical regulatory pathways.
