Targeting HAUSP: Killing Two Birds with One Stone

The cysteine protease deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP) has been fairly well characterized in recent years and has emerged as an important component of the p53-Mdm2-MdmX signaling pathway. HAUSP was first identified as a 135 kD cellular factor associated with the herpesvirus regulatory protein Vmw110. Interestingly, reduction or ablation of HAUSP leads to the DNA-damage-induced MdmX degradation and instability of Mdm2, leading to a robust stabilization of p53. Removal of HAUSP reduces the half-life of Mdm2 from 30 min to approximately 5 min. These four proteins, p53, Mdm2, MdmX, and HAUSP have a delicate, intimate balance that maintains p53 proteins levels and is critical for an appropriate DNA damage response to occur. And because of the strong p53 induction that occurs in the absence of HAUSP, it represents a potential chemotherapeutic target for the stabilization and activation of p53 in cells that retain a wildtype copy of the gene.