The effects of ionizing radiation on p53 and p21CIP1

Abstract

In response to ionizing radiation (IR) cells undergo cell cycle arrest and/or apoptosis. These responses are mediated by the tumor suppressor protein p53, and are thought to be essential for maintaining genomic stability and integrity. Although it has long been assumed that the mechanisms by which p53 regulates these processes were ubiquitous, the advent of new experimental techniques and technologies has begun to demonstrate variations. As such, the purpose of this thesis was to re-investigate the effects of IR on p53, and one of its key downstream targets, the cyclin dependent kinase inhibitor p21 CIPl, with some of the more recent observations in mind.

The results presented within this thesis contradict much of the previous data on the effects of IR on p53 and p21 CIPl; it is demonstrated that p53 activity and protein levels are unaltered in response to IR, and that p21 ClPl exists in a heterogeneous population of isoforms. Most importantly, it is shown that p21 CIPl may be differentially modified in response to IR. Based on the results contained within this thesis a theoretical model is proposed by which p53/p21ClPl mediated cell cycle arrest occurs in response to IR.