Control of p53 ubiquitination and nuclear export by MDM2 and ARF.

p53 and ARF-INK4a are the two most frequently altered loci in human tumors. The activity of p53 protein is inhibited during normal cell growth by the proto-oncoprotein MDM2 through either repression of p53-mediated transcription in the nucleus or proteasomal degradation of p53 protein in the cytoplasm. Responding to oncogenic signal-activated cell hyperproliferation, ARF-mediated antagonism of MDM2 inhibition results in p53 becoming active and its protein levels rising. The biochemical mechanisms of ubiquitination and nuclear export that underlie the functions of ARF and MDM2 in p53 control continue to emerge.