Mice and cell lines. Bone marrow macrophages were derived from various mouse strains, including Mavs / (Sun et al., 2006) , Mda5 / (Gitlin et al., 2006) , and Zbp1 / (Ishii et al., 2008) . Wild-type C57BL/6 and Tnfr1 / mice were from the Jackson Laboratory. Myd88 / /Trif / mice were obtained from G. Barton (University of California, Berkeley, Berkeley, CA). Irf1 / , Irf3 / , Irf5 / , and Irf 7 / mice were obtained from T. Taniguchi (University of Tokyo, Tokyo, Japan). Tbk1 / /Tnfr1 / mice were generated by crossing Tbk1 / mice (provided by W.-C. Yeh, University of Toronto, Toronto, Canada) with Tnfr1 / mice. Rip2 / mice were obtained from R. Medzhitov (Yale University, New Haven, CT). Nod1 / /Nod2 / mice were obtained from D. Portnoy (University of California, Berkeley, Berkeley, CA). Nalp3 / mice were obtained from V. Dixit (Genentech, South San Francisco, CA). ISRE-L929 IFN reporter cells were obtained from Gene Expression Profiling in Cells with Enhanced γ-Secretase Activity BACKGROUND: Processing by γ-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of γ-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of γ-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes and molecular functions transcriptionally affected by γ-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited γ-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to γ-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by γ-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. CONCLUSIONS/SIGNIFICANCE: Investigating the effects of γ-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of γ-secretase and its roles in cancer and Alzheimer's disease pathology. 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] .