Phenotypic Analysis of Mice with Reducedγ-Secretase show Possible Tumor Suppressant Properties

There were observed abnormalities in the phenotypical analysis of mice with targeted disruption in the γ-secretase complex. γ-Secretase, an aspartyl protease comprised of presenilin (PS), nicastrin (Nct), anterior pharynx defective-1 (Aph-1) and PS enhancer-2 (Pen-2), is an unusual enzyme required for the regulated intramembraneous proteolysis of a growing list of type I transmembrane proteins, such as members of the Notch and amyloid precursor protein (APP) family of proteins. While γ-secretase has been regarded as potential therapeutic targets for Alzhiemer's disease and some types of cancers, the function of this complicate protease is not well defined. Here, we assessed the phenotypic consequences of genetic reduction of γ-secretase activity using mice lacking one allele of PS, Nct, or Aph-1a to generate a series of mice with different levels of γ-secretase activity. Our results established that reduction of γ-secretase activity in mice increase risk of tumorigenesis and abnormal spleen growth in comparison to wild-type (wt) mice. All of the aged Nct^± mice suffered hyperproliferations in the squamous layers (some in the basal layers) of the epidermis. Neoplasia and Squamous cell carcinoma were also occurred in most of Nct^± mice. The spleen of Nct^± mice showed an increase in granulocytes and a decline in T-cells. These adverse effects in mice with decreased γ-secretase activity indicate that γ-secretase is involved in regulation of cell proliferation and can serve as a tumor suppressor in mammals. Administration methods for clinical use of the protease complex could prove to be a milestone for tumor specific deficiencies.