The p53 tumor suppressor is a transcription factor that exerts its anti-neoplastic effects by regulating the expression of specific mRNAs and miRNAs. Previous work from our lab using a temperature sensitive variant of p53 that permitted rapid and reversible control of p53 activity suggested that p53-induced mRNAs were unstable while miRNAs were stable. In this way, p53-induced mRNAs returned to baseline rapidly after transient p53 activation while p53-responsive miRNAs remained elevated, modulating subsequent p53 responses. In the present work, this model was tested using a reversible small molecule activator of p53 (Nutlin-3a) in HCT116 colon cancer cells. In addition, the p53 response was monitored in buccal epithelium and blood samples obtained throughout the course of daily radiation treatments in patients with acute myeloid leukemia in preparation for bone marrow transplantation. These models didn’t fully recapitulate earlier findings but provide important insight into the p53 response in vitro and in vivo.