• p53 tumor suppressor must be closely regulated.
  • This is the job of MDM2 (also known as HDM2 in human cells) and its partner MDMX
  • Most of the time, MDM2 binds to p53.
    • This has multiple effects.
      • First, one domain of MDM2 binds to the transactivation domain of p53, blocking its signaling action.
      • Another part of MDM2 holds a nuclear export signal, which is used to drag p53 out of the nucleus, away from the genes it activates, and into the cytoplasm.
      • Finally, in the cytoplasm, another domain of MDM2 and MDMX act as a ubiquitin ligase, adding ubiquitin to p53 and targeting it for destruction by proteasomes.

In some cases, p53 itself is corrupted, so the cell has no way of protecting itself. In other cases, cancer cells find ways of creating more MDM2, often by having multiple copies of the gene that encodes it. This extra MDM2 continually blocks the action of p53, allowing the cancer cell to grow unchecked.