Presenilins (PS, PS1/PS2) are necessary for the proteolytic activity of γ-secretase, which cleaves multiple type I transmembrane proteins including Alzheimer's β-amyloid precursor protein (APP), Notch, ErbB4, etc. Cleavage by PS/γ-secretase releases the intracellular domain (ICD) of its substrates. Notch ICD translocates into the nucleus to regulate expression of genes important for development. However, the patho/physiological role of other ICDs, especially APP ICD (AICD), in regulating gene expression remains controversial because evidence supporting this functionality stems mainly from studies performed under supraphysiological conditions. EGF receptor (EGFR) is up-regulated in a wide variety of tumors and hence is a target for cancer therapeutics. Abnormal expression/activation of EGFR contributes to keratinocytic carcinomas, and mice with reduced PS dosages have been shown to develop skin tumors. Here we demonstrate that the levels of PS and EGFR in the skin tumors of PS1^+/−/ PS2^−/− mice and the brains of PS1/2 conditional double knockout mice are inversely correlated. Deficiency in PS/γ-secretase activity or APP expression results in a significant increase of EGFR in fibroblasts. Importantly, we show that AICD mediates transcriptional regulation of EGFR. Furthermore, we provide in vivo evidence demonstrating direct binding of endogenous AICD to the EGFR promoter. Our results indicate an important role of PS/γ-secretase-generated APP metabolite AICD in gene transcription and in EGFR-mediated tumorigenesis.