Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

Introduction c-Secretase is an unconventional aspartyl protease (composed of PS1, NCT, Aph-1 and Pen2) with an intramembranous catalytic site that is typical of the class of intramembrane-cleaving proteases (I-CliPs) (for review, see [1, 2] ). Via the processing of its substrates and freeing of their intracellular domains (ICDs), c-secretase regulates a multitude of signaling pathways and biological processes by influencing gene transcription. This is exemplified by the processing of the Notch receptor and the Notch signaling pathway (for a review, see [3] ). After specific ectodomain shedding via tumor necrosis factor a converting enzyme (TACE) (Fig. 1, step 1) , Notch is further cleaved intramembraneously by c-secretase (Fig. 1, step 2) . The intracellular domain of Notch (NICD) is freed to enter the nucleus, where it interacts with the transcription factor CSL (Fig. 1, step 3 ). With help from the coactivator Mastermind, CSL is converted from a transcriptional repressor to a transcriptional activator. CSL as an activator leads to the expression of Notch target genes (Fig. 1, step 4) , like the Hes or Hey family. Hes1, a transcriptional repressor, inhibits the transcription of NC3C1 (Fig. 1, step 5 ). Enhanced c-secretase activity, through its cleavage of Notch, leads to increased transcription of specific genes (Fig. 1, step 4) that repress the expression of other genes (Fig. 1, step 6) to influence a multitude of biological processes. For example, the processing of Notch by c-secretase is crucial for hepatoblast differentiation [4] , epidermis and hair follicle differentiation [5] , alveolar differentiation in mammary glands [6] , maintenance of skin appendages [7] , intestinal stem cell specification [8] , induction of satellite cells after injury and maintenance [9] and neural specification of embryonic stem cells [10] .