Question 1

What does MDM2 do?

Accepted Answer

MDM2 is an E3 ubiquitin ligase that polyubiquitinates p53, targeting it for proteasomal degradation, and also directly inhibits p53's transcriptional activation domain. Together these mechanisms form the principal p53 negative feedback loop: p53 activates MDM2, which then degrades p53.

Question 2

How does MDM2 amplification cause cancer without TP53 mutation?

Accepted Answer

MDM2 amplification leads to excess MDM2 protein that constitutively degrades wild-type p53, functionally inactivating the p53 pathway without requiring TP53 mutation. MDM2-amplified tumours — particularly liposarcomas — therefore retain wild-type TP53 and are rational targets for MDM2 inhibitors.

Question 3

Are there drugs targeting MDM2?

Accepted Answer

MDM2 inhibitors (idasanutlin, milademetan, navtemadlin) occupy the p53-binding pocket of MDM2, blocking the protein-protein interaction and stabilising p53. Clinical trials are ongoing in MDM2-amplified liposarcoma and AML, where responses in TP53-wild-type patients have been observed.

MDM2 Gene Function

Overview

More Tumor Suppressor Genes