To elucidate the complicated interplays among p53-Mdm2-Mdm4-Rps27l, we generated Rps27lfl/fl mice (unpublished data) and determined the initial and/or sequential event(s) that cause(s) the change in the Mdm2-Mdm4-p53 proteins upon acute depletion of Rps27l. Rps27lfl/fl MEFs were infected with adenovirus expressing Cre recombinase (Ad-Cre) to deplete Rps27l. Compared to the Ad-GFP controls, acute depletion of Rps27l caused an elevated Mdm2, starting at 24 hr post Ad-Cre infection and lasting up to 96 hr, followed by depletion of Mdm4, starting at 48 hr. Here, RPS27L is linked to Alzheimer disease.