The p53 paddy wagon: COP1, Pirh2 and MDM2 are found resisting apoptosis and growth arrest.

For years, the growth inhibitory effects of the tumor suppressor p53 were thought to be antagonized predominantly by the ubiquitin ligase, MDM2. It has long been established that MDM2 physically associates with p53 and targets this tumor suppressor for proteasomal degradation. In light of recent findings, it now appears that MDM2 may not be the only ubiquitin ligase that negatively controls p53 function. Two recently discovered proteins, Pirh2 and COP1, are also believed to facilitate p53 degradation via the ubiquitin-proteasome pathway. Both proteins are upregulated by p53 as well as genotoxic stress and each has been found to directly promote p53 ubiquitination and degradation. Future studies in this field will now face the challenge of elucidating the physiological significance of three molecules all apparently able to independently facilitate p53 degradation and abrogate its function.