MDM2

Function

MDM2 binds the transactivation domain of p53, masks its ability to activate transcription, shuttles it out of the nucleus, and ubiquitinates it for proteasomal destruction. The gene’s own transcription is activated by p53, so the pair forms a negative feedback loop: p53 rises, drives MDM2 expression, and MDM2 then cuts p53 back down. DNA damage interrupts the loop - ATM phosphorylates both proteins at the residues that matter, and the stress-sensing protein p14ARF sequesters MDM2 - so p53 accumulates until the damage signal clears.

In cancer

The MDM2 gene is on chromosome 12q and is amplified in a substantial fraction of sarcomas and in subsets of many other tumors. Amplified MDM2 removes functional p53 in cells whose TP53 gene is intact, which is the same endpoint as TP53 mutation reached by a different route. MDM2 inhibitors (nutlins and their clinical successors) block the p53-binding pocket, release p53 in MDM2-amplified tumors, and are in clinical development.

Notes

• Human gene symbol: MDM2; UniProt Q00987; 491 amino acids; RING-type E3 ubiquitin ligase.
• Named for “murine double minute”, the chromosome artifact from which the mouse gene was first cloned.