Tweaking p53 Without Accelerating Aging

The p53 tumor suppressor plays a critical role in cancer formation, and many anticancer strategies aim to activate p53 in order to curb tumor formation. Mdm2 is a key inhibitor of p53 and therefore an attractive target to modulate p53 activity in cells. However, conflicting evidence exists regarding whether or not p53-mediated tumor suppression comes at the cost of accelerated aging.

To analyze the effects of reduced Mdm2 levels on tumorigenesis – as well as the potential for unwanted side effects – Dr. Perry's team used mdm2-hypomorphic mice (that express less Mdm2 protein than normal mice) which have elevated levels of wild-type p53 activity. The researchers found that even a modest decrease (about 20%) in Mdm2 effectively prevents tumor formation and does not lead to premature aging.

Dr. Perry emphasizes that "many people develop cancer at a young age due to increased expression of Mdm2. The possibility that inhibitors of Mdm2 could delay cancer in such people without causing detrimental side effects is bolstered by our demonstration that mice expressing 30-80% the normal level of Mdm2 develop fewer tumors than wild type mice, yet age normally."