Insight into the Regulation of a Key Tumor Suppressor

A new study published in the online open-access journal PLoS Biology explores a longstanding paradox in the regulation of a key tumor suppressor protein called p53. Min Hu, Yigong Shi, and their colleagues applied structural and mutational approaches to shed light on the regulation of a crucial regulatory pathway. Mutations that disable p53, which also plays a crucial role in regulating cell growth, are the most common mutations in many human cancers.

When cell damage occurs, p53 activates one of several stress-induced genes. In healthy cells, p53 levels are minimized by proteins that mark the protein for degradation such as MDM2. Intriguingly, by promoting the transcription of the MDM2 protein, p53 is responsible for its own regulation. Another protein that also plays a role in p53 regulation is an enzyme called HAUSP (herpesvirus-associated ubiquitin-specific protease) which can bind to p53, stabilize the protein, and promote cell death and cell growth arrest. But HAUSP can also stabilize MDM2. These seemingly contradictory actions led the researchers to wonder exactly what state p53 is left in once MDM2 and HAUSP have finished competing with one another.

Hu et al. show that both p53 and MDM2 bind to the same location on the HAUSP protein domain in a mutually exclusive manner. They also show that a conserved short amino acid signature appears to be responsible for this binding. Analysis of the molecular basis of their differential binding revealed that MDM2 binds HAUSP more frequently. And because MDM2 consistently formed stable complexes with HAUSP despite the presence of ten times more p53 peptides, it was clear that MDM2 binds to the HAUSP with a higher affinity. This suggests how HAUSP may regulate the critically important p53–MDM2 pathway.

This study suggests that HAUSP likely targets MDM2 under normal physiological conditions, and provides a valuable framework for probing the function of the p53–MDM2 pathway. The differential binding properties of p53 and MDM2 also suggest promising drug-screening targets. Given MDM2’s negative impact on p53, it may be that inhibiting HAUSP, and thus MDM2, could counteract mutations that interfere with p53 function, and give this tumor suppressor the boost it needs to do its job.

Citation : Hu M, Gu L, Li M, Jeffrey PD, Gu W, et al. (2006) Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: Implications for the regulation of the P53–MDM2 pathway. PLoS Biol 4(2): e27.

CONTACT:
Yigong Shi
Princeton University
Washington Road
Princeton, NJ USA 08544
+1-609-258-6071
YShi@molbio.Princeton.edu