MDM2 regulates RB levels during genotoxic stress.

The retinoblastoma tumour suppressor protein (RB) regulates a number of diverse cellular functions including differentiation, angiogenesis, chromatin remodelling, senescence and apoptosis. The best-characterised function of RB is cell cycle regulation, and it has been considered a phosphoprotein regulated by cyclin-dependent kinases. In its hypophosphorylated form, RB binds the transcription factor E2F1, arresting the cell cycle in the G1 phase. Here, we show that MDM2 controls the cell cycle through synthesis and degradation of RB protein in a cell cycle condition-dependent fashion. MDM2 induces G1 cell cycle arrest by enhancing the translation of the RB mRNA under genotoxic stress. Translation requires direct interaction between the RB mRNA and the MDM2 protein that accompanies the RB mRNA to the polysomes. However, MDM2 ubiquitinates and degrades RB protein at the G2/M phase under genotoxic stress. The ATM phosphomimetic mutant MDM2(S395D) corroborates that the effect on the RB levels is dependent on the DNA damage. These results provide the basis of a dual regulatory mechanism by which MDM2 controls cell cycle progression during DNA damage.